Drug granule coatings that impart smear resistance during mechanical compression

ABSTRACT

A drug formulation is disclosed comprising granules having a substrate and a coating, said granule substrate comprising a solubilizing surfactant or a low solubility therapeutic drug, or both, and said granule coating comprising a hydrophilic polymer. Also disclosed is a drug formulation consisting of a tablet core made by mechanical compression, wherein said tablet core comprises granules having a substrate and a coating, said granule substrate comprising a solubilizing surfactant or a low solubility therapeutic drug, or both, and said granule coating comprising a hydrophilic polymer. Also disclosed is a dosage form for oral administration of topiramate, comprising a tablet core and an osmotic delivery system. Methods for controlling topiramate release patterns by altering the composition of the topiramate dosage form are also disclosed.

CROSS REFERENCE TO RELATED APPLICATION

This application claims the benefit of U.S. Provisional Application No.60/533,112, filed on Dec. 29, 2003 and U.S. Provisional Application No.60/533,470, filed on Dec. 29, 2003, which are incorporated by referenceherein in thier entirety.

FIELD OF THE INVENTION

A drug formulation is disclosed comprising a compressed tablet corecomprising a solubilizing agent, preferably a surfactant, and a lowsolubility therapeutic drug, in which one or both of the therapeuticdrug and solubilizing agent are in coated granules. Also disclosed is acontrolled release dosage form for oral administration of topiramate,comprising the tablet core. A method is disclosed for controllingtopiramate release patterns by modifying the composition of the coatedgranules in the controlled release dosage form.

BACKGROUND OF THE INVENTION

Various dosage forms for the controlled release of pharmaceutical agentsare known. While a variety of dosage forms for delivering certain drugsmay be known, not every drug may be suitably delivered from those dosageforms because of solubility, metabolic processes, absorption and otherphysical, chemical and physiological parameters that may be unique tothe drug and the mode of delivery.

Dosage forms using surfactants are known in the art. U.S. Pat. No.6,569,463 describes using drug formulations consisting of coatedgranules, in which the coating consists of at least one surfactant andpreferably a mixture of the surfactant with a hydrophobic drug and alipophilic additive. This substrate coating facilitates rapid dispersionand provides rapid, sustained solubilization of the drug in the absenceof liquid ingredients. The lipophilic additive further enhancessolubilization of the drug or promotes dispersion in vivo.

Dosage forms that incorporate a low solubility drug, including high drugloading for the dosage form, continue to be an elusive goal forcontrolled release delivery technology, in which dosage forms generallytend to be too large for patients to willingly swallow them.

Dosage forms made in the form of an osmotic delivery system are known tothe delivery art in U.S. Pat. Nos. 3,845,770 and 3,916,899, both issuedto patentees Felix Theeuwes and Takeru Higuchi. The dosage formdisclosed and claimed in these patents comprises a semipermeable wallthat surrounds a compartment containing a beneficial agent, usually abeneficial drug (e.g. a pharmaceutical or therapeutic drug).

The wall is permeable to the passage of an external fluid andsubstantially impermeable to the passage of a beneficial drug. There isat least one passageway through the wall for delivering the beneficialagent from the dosage form. The dosage form releases the beneficialagent by fluid being continuously imbibed through the wall into thedosage form at a rate determined by the permeability of thesemipermeable wall and the osmotic pressure gradient across the wall.This physical-chemical action produces a solution containing thebeneficial agent that is hydrodynamically dispensed through thepassageway from the dosage form.

The above described patents also are useful for delivering a beneficialagent that exhibits a low solubility drug in an external fluid imbibedinto the dosage form. The dosage form delivers such beneficial agent byblending the drug with an osmotically—effective solute, known also asosmagent. The osmagent in the dosage form is a substantial motive forceas it exhibits an osmotic pressure gradient across the wall of thedosage form, and it imbibes fluid into the dosage form. The osmagentproduces a solution with the imbibed fluid that is osmotically deliveredfrom the dosage form concomitantly transporting therewith undissolved,or dissolved drug from the dosage form.

The dosage form of these patents significantly advanced the deliveryart, and its delivery kinetics are ideal for many drugs. However, when alow solubility drug is mixed with an osmagent to produce an equilibriumratio, the resulting drug solubility in the presence of the osmagentoften is still too low, usually less than 100 mg/ml. In this instance,this drug cannot be released at a controlled rate over a prolongedperiod of time. When the resulting beneficial agent's solubility is low,it is difficult to deliver the beneficial agent at meaningfultherapeutic rates.

Another improvement is described in U.S. Pat. No. 4,755,180. This patentteaches encapsulated osmotic agents as a means to improve the deliverykinetics of the dosage form. The shortcomings of this approach, however,are all too apparent in that it is still based on controlling thedelivery rate solely by means of an osmotic gradient across the outerwall of the dosage form.

Various devices in which a drug composition is delivered as a slurry,suspension or solution from a small exit orifice by the action of anexpandable layer are described in U.S. Pat. Nos. 5,633,011; 5,190,765;5,252,338; 5,620,705; 4,931,285; 5,006,346; 5,024,842; and 5,160,743.Typical devices include a tablet comprising an expandable push layer anda drug layer, which tablet is surrounded by a semipermeable membranehaving a delivery orifice. In certain instances, the tablet is providedwith a subcoat to delay release of the drug composition to theenvironment of use.

Devices in which a drug composition is delivered in a dry state from alarge exit orifice by the action of an expandable layer are described inU.S. Pat. Nos. 4,892,778, 4,915,949 and 4,940,465 and 5,023,088. Thesereferences describe a dispenser for delivering a beneficial agent to anenvironment of use that includes a semipermeable wall containing a layerof expandable material that pushes a dry drug layer composition out ofthe compartment formed by the wall. The exit orifice in the device issubstantially the same diameter as the inner diameter of the compartmentformed by the wall. In such devices, a substantial area of the druglayer composition is exposed to the environment of use leading torelease performance that can be subject to the stirring conditions insuch environment.

Other similar devices have delivered drug by expelling discrete drugcontaining tablets at a controlled rate over time. U.S. Pat. Nos.5,938,654; 4,957,494; 5,023,088; 5,110,597; 5,340,590; 4,824,675; and5,391,381.

Other devices attempt to deliver low solubility drugs by incorporatingliquid drug formulations that are released at a controlled rate overtime. These devices are disclosed in U.S. Pat. Nos. 4,111,201;5,324,280; 5,413,672; 6,174,547. However, such liquid osmotic deliverysystems are limited in the concentration of drug in the liquidformulation and hence, the drug loading available, leading to deliverysystems that can be of an unacceptably large size.

Still other delivery systems utilize a liquid carrier to deliver tinytime pills suspended within the liquid carrier. Such devices aredisclosed U.S. Pat. Nos. 4,853,229 and 4,961,932. These suspensionsrequire that the therapeutic dose of pharmaceutical agent be dispensedby volume with measuring devices such as graduated cylinders ormeasuring spoons, a dispensing process that can be messy andinconvenient for the patient to administer.

While dosage forms delivering the drug composition to the environment ofuse in the dry state through a large delivery orifice may providesuitable release of drug over a prolonged period of time, the exposureof the drug layer to the variably turbulent fluid environment of usesuch as the upper gastrointestinal tract may result inagitation-dependent release of drug that in some circumstances isdifficult to control. Moreover, such dosage forms delivering in the drystate into a semisolid environment lacking sufficient volumes of bulkwater such as in the lower colonic environment of the gastrointestinaltract may have difficulty liberating the dry dispensed drug compositioninto the environment as the high solids content composition tends toadhere to the dosage form at the site of the large orifice. Accordingly,it may be advantageous to release the drug as a well-hydrated slurry orsuspension that may provide a means to control the rate of expansion ofthe push layer and in combination with the smaller size of the exitorifice in the dosage form to minimize effects of localized stirringconditions on delivery performance. Move this paragraph to just before[00012]??

The dosage forms described above deliver therapeutic agents at asubstantially zero order rate of release. Recently, dosage forms havebeen disclosed for delivering certain drugs at substantially ascendingrates of release such as ALZA Corporation's Concerta® methylphenidateproduct. PCT Published Application Nos. U.S. 99/11920 (WO 9/62496); U.S.97/13816 (WO 98/06380); and U.S. 97/16599 (WO 98/14168). Such discloseddosage forms involve the use of multiple drug layers with sequentiallyincreasing concentrations of drug in each drug layer to produce theincreasing delivery rate of drug over time. While such multi-layertablet constructions represent a significant advancement to the art,these devices also have limited capability of delivering lowly solublepharmaceutical agents, particularly those associated with relativelylarge doses of such agents, in a size that is acceptable for patients toswallow.

Thus, there remains a need for a means to manufacture and deliver highdoses of lowly soluble drug compounds at various delivery patterns thatare convenient and feasible for patients in need to swallow. The needincludes effective dosing methods, dosage forms and devices that willpermit the controlled release of the drug compounds over a prolongedperiod of time by increasing the solubility of the active agent in orderto increase the time between dosing, preferably twice a day and mostpreferably to obtain a once-a-day dosing regimen. Such dosage formsshould preferably have the option of delivering at a substantially zeroorder rate of release, ascending or other hybrid delivery rate patternappropriate for the therapeutic agent being delivered.

SUMMARY OF THE INVENTION

The present invention is directed to a drug composition comprisinggranules having a substrate and a coating, the granule substratecomprising a solubilizing agent, preferably a surfactant, or a lowsolubility therapeutic drug, or both, and the granule coating comprisinga hydrophilic polymer.

One present invention is a drug formulation comprising a tablet coremade by mechanical compression, in which the tablet core comprisesgranules having a substrate and a coating, the granule substratecomprising a solubilizing agent, preferably a surfactant, or a lowsolubility therapeutic drug, or both, and the granule coating comprisinga hydrophilic polymer.

Another present invention is a drug formulation comprising a capsule,wherein said capsule comprises granules having a substrate and acoating, the granule substrate comprising a solubilizing agent,preferably a surfactant, or a low solubility therapeutic drug, or both,and the granule coating comprising a hydrophilic polymer.

An embodiment of the invention is a drug formulation, in which thegranule substrate comprises a surfactant. Another embodiment is a drugformulation, in which the granule substrate further comprises the drug.In yet another embodiment is a drug formulation, in which the granulesubstrate comprises the drug. A related embodiment is a drugformulation, in which the amount of solubilizing agent, preferablysurfactant, in the granule substrate is between about 1% and about 90%by weight. A preferred embodiment is a drug formulation in which theamount of solubilizing agent, preferably surfactant, in the granulesubstrate is between about 5% and about 50% by weight.

Another aspect of the invention is a drug formulation, in which thesolubilizing agent, preferably surfactant, is selected from the groupconsisting of polyoxyl 40 stearate, polyoxyl 50 stearate, triblockco-polymers of ethylene oxide/propylene oxide/ethylene oxide, sorbitanmonopalmitate, sorbitan monostearate, glycerol monostearate,polyoxyethlene stearate, polyoxyethylene 40 sorbitol lanolin derivative,polyoxyethylene 75 sorbitol lanolin derivative, polyoxyethylene 6sorbitol beeswax derivative, polyoxyethylene 20 sorbitol beeswaxderivative, polyoxyethylene 20 sorbitol lanolin derivative,polyoxyethylene 50 sorbitol lanolin derivative, polyoxyethylene 23lauryl ether, polyoxyethylene 23 lauryl ether, polyoxyethylene 2 cetylether, polyoxyethylene 10 cetyl ether, polyoxyethylene 20 cetyl ether,polyoxyethylene 2 stearyl ether, polyoxyethylene 10 stearyl ether,polyoxyethylene 20 stearyl ether, polyoxyethylene 21 stearyl ether,polyoxyethylene 20 oleyl ether, polyoxyethylene 40 stearate,polyoxyethylene 50 stearate, polyoxyethylene 100 stearate, sorbitanmonopalmitate, sorbitan monostearate, sorbitan tristearate,polyoxyethylene 4 sorbitan monostearate, polyoxyethylene 20 sorbitantristearate, and mixtures thereof. A preferred embodiment is a drugformulation, in which the surfactant is selected from the groupconsisting of polyoxyl 40 stearate, polyoxyl 50 stearate, di-blockcopolymers of ethylene oxide:propylene oxide, a:b:a triblock copolymersof ethylene oxide:propylene oxide:ethylene oxide and mixtures thereof.

Another aspect of the invention is a drug formulation, in which thegranule substrate further comprises a viscosity agent. A furtherembodiment of the invention is a drug formulation, in which the granulesubstrate further comprises a binding agent. Another further embodimentis a drug formulation, in which the granule substrate further comprisesan osmotic agent, and more preferably, an osmotic agent selected fromthe group consisting of sodium chloride, sucrose, sorbitol, andmannitol.

Another aspect of the invention is a drug formulation, in which thetherapeutic agent in the absence of solubilizing agent, preferably,surfactant has aqueous solubility that is between about 1 μg/ml andabout 100 mg/ml. A preferable embodiment is a drug formulation, in whichthe therapeutic agent in the absence of solubilizing agent, preferably,surfactant, has aqueous solubility that is between about 1 μg/ml andabout 50 mg/ml.

Another embodiment of the invention is a drug formulation, in which thegranule coating is continuous. An alternative embodiment is a drugformulation, in which the granule coating is discontinuous.

Another embodiment of the invention is a drug formulation, in which thegranule coating is water-soluble, and more preferably, in which thegranule coating is comprised of a compound selected from the groupconsisting of polyvinyl pyrrolidone, polyethylene oxide, polyethyleneglycol, polyvinyl alcohol, polyvinyl alcohol-polyethylene glycolcopolymer, vinyl acetate-vinyl pyrrolidone copolymer, hydroxypropylcellulose, hydroxypropyl methylcellulose, methylcellulose, hydroxyethylcellulose, sodium carboxymethylcellulose, calciumcarboxymethylcellulose, polyvinyl acetate polyethylene glycolco-polymer, starches, maltodextrins, sugars, sorbitol, mannitol,sucrose, gelatin, casein, natural gums, alginates and mixtures thereof.

A related embodiment of the invention is a drug formulation, in whichthe granule coating is water insoluble, and more preferably, in whichthe granule coating is comprised of a compound selected from the groupconsisting of a polyether, a polyester, cellulose acetate, celluloseacetate butyrate, a polyacrylate and mixtures thereof. Anotherembodiment is a drug formulation, in which the granule coating isadditionally comprised of a compound selected from the group consistingof polyethylene glycol, polyoxyethylene-polyoxypropylene copolymer,hydroxypropyl cellulose, glycerin, a citric acid ester, and dibutylsebacate. In a preferred embodiment is a drug formulation, in which thepolyether of the granule coating is ethyl cellulose. In anotherpreferred embodiment is a granule coating, in which the polyester ispolyvinyl acetate. In yet another preferred embodiment is a granulecoating, in which the polyacrylate is anethylacrylate-methylmethacrylate copolymer. In yet another preferredembodiment is a granule coating, in which the citric acid ester istriethyl citrate or acetyl triethylcitrate,

Another embodiment of the invention is a drug formulation, in which thegranule coating is a single layer. A preferable embodiment is a drugformulation, in which the single-layer coating is comprised of polyvinylpyrrolidone or polyethylene oxide. In another embodiment is a drugformulation, in which the single-layer coating is between about 1% andabout 3% of the granule weight, or at least about about 24% of thegranule weight.

Another embodiment is a drug formulation, in which the granule coatingis a multiplicity of layers. A preferred embodiment is a drugformulation, in which the coating comprises two layers. A more preferredembodiment is a drug formulation, in which the coating is comprised ofan outer layer of methylcellulose and an inner layer of polyethyleneoxide or polyvinyl pyrrolidone.

In an embodiment is a dosage form for oral administration of topiramate,comprising any of the foregoing drug formulations, in which the drug istopiramate.

Another present invention is a dosage form for oral administration oftopiramate, comprising a tablet core made by mechanical compression, inwhich the tablet core comprises granules having a substrate and acoating, said granule substrate comprising a solubilizing agent,preferably surfactant, or topiramate, or both, and said granule coatingcomprising a hydrophilic polymer.

An embodiment of the invention is a topiramate dosage form, furthercomprising an osmotic delivery system and a tablet core, wherein theosmotic delivery system and the tablet core are surrounded by asemipermeable membrane having a delivery port through the membrane.

Another embodiment of the invention is a topiramate dosage form, inwhich the tablet core is incorporated into a matrix delivery system. Thematrix system may be either an erodible matrix delivery system or anon-erodible matrix delivery system.

Another embodiment of the invention is a topiramate dosage form, inwhich the dosage form is a controlled release topiramate dosage form.

Another embodiment of the invention is a controlled release topiramatedosage form, in which the solubilizing agent, preferably surfactant, isselected from the group consisting of polyoxyl 40 stearate, polyoxyl 50stearate, triblock co-polymers of ethylene oxide/propyleneoxide/ethylene oxide, sorbitan monopalmitate, sorbitan monostearate,glycerol monostearate, polyoxyethlene stearate, polyoxyethylene 40sorbitol lanolin derivative, polyoxyethylene 75 sorbitol lanolinderivative, polyoxyethylene 6 sorbitol beeswax derivative,polyoxyethylene 20 sorbitol beeswax derivative, polyoxyethylene 20sorbitol lanolin derivative, polyoxyethylene 50 sorbitol lanolinderivative, polyoxyethylene 23 lauryl ether, polyoxyethylene 23 laurylether, polyoxyethylene 2 cetyl ether, polyoxyethylene 10 cetyl ether,polyoxyethylene 20 cetyl ether, polyoxyethylene 2 stearyl ether,polyoxyethylene 10 stearyl ether, polyoxyethylene 20 stearyl ether,polyoxyethylene 21 stearyl ether, polyoxyethylene 20 oleyl ether,polyoxyethylene 40 stearate, polyoxyethylene 50 stearate,polyoxyethylene 100 stearate, sorbitan monopalmitate, sorbitanmonostearate, sorbitan tristearate, polyoxyethylene 4 sorbitanmonostearate, polyoxyethylene 20 sorbitan tristearate, and mixturesthereof. A preferred embodiment is a topiramate dosage form, in whichthe solubilizing agent, preferably surfactant, is selected from thegroup consisting of polyoxyl 40 stearate, polyoxyl 50 stearate, di-blockcopolymers of ethylene oxide:propylene oxide, a:b:a triblock copolymersof ethylene oxide:propylene oxide:ethylene oxide, and mixtures thereof.Most preferably, is a topiramate dosage form, in which the solubilizingagent, preferably surfactant, is a polyoxyethylene-polyoxypropylenecopolymer. Another embodiment is a topiramate dosage form, in which theweight ratio of the polyoxyethylene-polyoxypropylene copolymer totopiramate is up to about 3.0.

Another embodiment of the invention is a controlled release topiramatedosage form, in which the amount of solubilizing agent, preferablysurfactant, is between about 5% and about 90% by weight of the core, andpreferably, between about 5% and about 50% by weight of the core.

Another embodiment is a controlled release topiramate dosage form, inwhich the granule coating is continuous, or alternatively, in which thegranule coating is discontinuous.

Another embodiment is a controlled release topiramate dosage form, inwhich the granule coating is water soluble and preferably, is comprisedof a compound selected from the group consisting of polyvinylpyrrolidone, polyethylene oxide, polyethylene glycol, polyvinyl alcohol,polyvinyl alcohol-polyethylene glycol copolymer, vinyl acetate-vinylpyrrolidone copolymer, hydroxypropyl cellulose, hydroxypropylmethylcellulose, methylcellulose, hydroxyethyl cellulose, sodiumcarboxymethylcellulose, calcium carboxymethylcellulose, polyvinylacetate polyethylene glycol co-polymer, starches, maltodextrins, sugars,sorbitol, mannitol, sucrose, gelatin, casein, natural gums, alginates,and mixtures thereof.

An alternate embodiment is a controlled release topiramate dosage form,in which the granule coating is water insoluble and preferably, iscomprised of a compound selected from the group consisting of polyetherssuch as ethyl cellulose, polyesters such as polyvinyl acetate, celluloseacetate, cellulose acetate butyrate, polyacrylates such as ethylacrylate methylmethacrylate copolymers and mixtures thereof. Anembodiment is a topiramate dosage form, in which the granule coating is,in addition to the ingredients above, is additionally comprised of acompound selected from the group consisting of polyethylene glycol,polyoxyethylene-polyoxypropylene copolymer, hydroxypropyl cellulose,glycerin, citric acid esters such as triethyl citrate and acetyltriethylcitrate, and dibutyl sebacate.

Another embodiment of the invention is a controlled release controlledrelease dosage form, in which the granule coating is comprised of asingle layer. Another embodiment is a topiramate dosage form, in whichthe single-layer coating is comprised of polyvinyl pyrrolidone orpolyethylene oxide. Another embodiment is a topiramate dosage form, inwhich the single-layer coating is up to about 3% of the granule weight,or up to about 30% of the granule weight.

Another embodiment is a controlled release topiramate dosage form, inwhich the granule coating is comprised of a multiplicity of layers. Apreferable embodiment is a topiramate dosage form, in which the coatingcomprises two layers. A more preferable embodiment is a topiramatedosage form, in which the coating is comprised of an outer layer ofmethylcellulose and an inner layer of polyethylene oxide or polyvinylpyrrolidone. Another embodiment is a topiramate dosage form, comprisingan expandable layer, in which the semipermeable wall is positioned overat least a portion of the expandable layer.

An embodiment of the invention is a controlled release topiramate dosageform, in which the granule substrate comprises both topiramate and asoluvbilizing agent, preferably a surfactant. Another embodiment is acontrolled release topiramate dosage form, in which the granulesubstrate further comprises a viscosity agent. Another embodiment is acontrolled release topiramate dosage form, in which the granulesubstrate further comprises a binding agent.

Another embodiment is a controlled release topiramate dosage form, inwhich the release rate of topiramate is at its maximum value for atleast two hours in an in vitro release rate assay. Additionalembodiments are controlled release topiramate dosage forms, in which therelease rate of topiramate is at its maximum value for at least aboutthree hours, about four hours, about six hours, about eight hours, aboutten hours and at least about 12 hours in an in vitro release rate assay.

In additional embodiments of the invention are controlled releasetopiramate dosage forms, in which the maximum release rate of topiramateis reached after about 1 hour, about 1.5 hours, about 2 hours, about 2.5hours, about 3 hours, about 4 hours, about 5 hours, about 6.5 hours,about 8 hours, about 10 hours, about 12 hours, about 14 hours and about16 hours in an in vitro release rate assay.

In one embodiment of the present invention is a drug compositioncomprising granules having a substrate and a coating, said granulesubstrate comprising a low solubility therapeutic drug and optionally asolubilizing agent, and said granule coating comprising one or morelayers, wherein each granule coating layer comprises an independentlyselected hydrophilic polymer and wherein the drug composition possessesa dissolution rate of the therapeutic drug, a time to maximum release ofthe therapeutic drug and a period of therapeutic drug delivery (when thedrug composition is tested in an in vitro assay or administered to asubject).

In another embodiment of the present invention is a drug compositioncomprising granules having a substrate and a coating, said granulesubstrate comprising a low solubility therapeutic drug and optionally asolubilizing agent, and said granule coating comprising one or morelayers, wherein each granule coating layer comprises an independentlyselected hydrophilic polymer and wherein the drug composition whensubjected to a measurement of dissolution exhibits a a dissolution rateof the therapeutic drug, a time to maximum release of the therapeuticdrug and a period of therapeutic drug delivery.

In an embodiment of the present invention is a dosage form comprising

-   (a) a core comprising a drug composition, wherein the drug    compositions comprise granules having a substrate and a coating,    said granule substrate comprising a low solubility therapeutic drug    and optionally a solubilizing agent, and said granule coating    comprising one or more layers, wherein each granule coating layer    comprises an independently selected hydrophilic polymer;-   (b) a semi-permeable wall surrounding the core; and-   (c) an exit orifice through the semi-permeable wall for releasing    the drug compositions from the dosage form over a prolonged period    of time.

In an embodiment of the present invention is a dosage form wherein thenumber of granule coating layers is selected to decrease the dissolutionrate of the therapeutic drug or to increase the time to maximum releaserate of the therapeutic drug or to increase the period of therapeuticdrug delivery or decrease the magnitude of the maximum release rate ofthe therapeutic drug.

In another embodiment of the present invention is a dosage form whereinthe granule coating comprises one layer and wherein the hydrophilicpolymer is selected to decrease the dissolution rate of the therapeuticdrug or increase the time to maximum release rate of the therapeuticdrug or increase the period of therapeutic drug delivery or decrease themagnitude of the maximum release rate of the therapeutic drug.

In another embodiment of the present invention is a dosage form whereinthe granule coating comprises one layer and wherein the amount of saidcoating is selected decrease the dissolution rate of the therapeuticdrug or increase the time to maximum release rate of the therapeuticdrug or increase the period of therapeutic drug delivery or decrease themagnitude of the maximum release rate of the therapeutic drug.

In another embodiment of the present invention is a dosage form whereinthe the dissolution rate of the therapeutic drug or the time to maximumrelease rate of the therapeutic drug or the period of therapeutic drugdelivery or the magnitude of the maximum release rate of the therapeuticdrug is controlled by varying one or more of (a) the number of coatinggranule layers, (b) the amount of each coating granule layer or (c) thehydrophilic polymer of each coating granule layer.

In an embodiment of the present invention is a dosage form wherein thetherapeutic drug is topiramate, wherein the granule coating comprisesone layer and wherein the hydrophillic polymer is selected from thegroup consisting of methylcellulose and polyvinylpyrolidone.

In an embodiment of the present invention is a dosage form wherein theamount of granule coating is in the range of between about 2.5% andabout 23% by weight. In another embodiment of the present invention is adosage form wherein the amount of granule coating is in the range ofbetween about 2.5% and about 23% by weight.

In an embodiment of the present invention is a dosage form wherein thegranule coating comprises one layer and the hydrophilic polymer isselected from the group consisting of (a) methylcellulose in an amountin the range of between about 2.5% and about 13% by weight, (b)polyvinylpyrolidone in an amount in the range of between about 3% andabout 23% by weight and (c) polyethylene oxide in an amount in the rangeof about 5% to about 15% by weight.

In another embodiment of the present invention is a dosage form whereinthe granule coating comprises one layer and the hydrophilic polymer ismethylcellulose present in an amount of about 3% by weight.

Another present invention is a method for controlling release patternsof a low solubility therapeutic drug, preferably topiramate, from acontrolled release dosage form, comprising:

-   (a) preparing granule substrates comprising topiramate and a    solubilizing agent, preferably surfactant,-   (b) coating the granule substrates,-   (c) mechanically compressing the coated granules to produce a tablet    core,-   (d) mechanically compressing the tablet core with a push layer and-   (e) surrounding the tablet core and push layer by a semipermeable    membrane having a delivery port across the membrane.

A preferred embodiment of the invention is a method for controlling therelease patterns of topiramate, in which preparing coated granulesfurther comprises:

-   (a) mixing topiramate with a solubilizing agent, preferably    surfactant, and a solvent,-   (b) forming a damp mass,-   (c) drying the mass,-   (d) sieving the dried mass to form granule substrates,-   (e) transferring the granule substrates to a fluid bed granulator,    and-   (f) spray-coating the granule substrates with a spray-coating    mixture to produce coated granules.

Another embodiment of the invention is a method for controlling releasepatterns of topiramate, in which the content and amount of the granulecoating is selected to increase the amount of time to reach the maximumrelease rate of topiramate in an in vitro release rate assay. Analternate embodiment is a method of selecting the content and amount ofthe granule coating to modulate the period of time that the release rateof topiramate is at its maximum value in an in vitro release rate assay.Another embodiment is a method selecting the content and amount of thegranule coating to modulate the magnitude of the maximum release rate oftopiramate in an in vitro release rate assay.

Another embodiment of the invention is a method for controlling releasepatterns of topiramate, in which the weight ratio of the solubilizngagent, preferably, surfactant, to topiramate in the granule substrate isselected to modulate the amount of time that the release rate oftopiramate is at its maximum value in an in vitro release rate assay.Alternate embodiments are methods of modifying the weight ratio of thesolubilizing agent, preferably, surfactants to topiramate in the granulesubstrate to modulate the period of time that the release rate oftopiramate is at its maximum value release patterns of topiramate, orthe magnitude of the maximum release rate of topiramate in an in vitrorelease rate assay.

An additional embodiment of the invention is a method for controllingrelease patterns of topiramate, comprising the additional step ofspraying-coating the coated granules with a second spray-coating mixtureto produce coated granules having an outer coating layer and an innercoating layer. A related embodiment is a method of selecting the contentand amount of the outer coating layer of the granule coating to increasethe amount of time to reach the maximum release rate of topiramate in anin vitro release rate assay. Alternate embodiments are methods ofmodifying the content and amount of the outer coating layer of thegranule coating to modulate the period of time that the release rate oftopiramate is at its maximum value or the magnitude of the maximumrelease rate of topiramate in an in vitro release rate assay.

The present invention is further directed to a drug compositioncomprising a pharmaceautical agent and a solubilizing agent, wherein thepharmaceutical agent is selected from a low solubility pharmaceuticalagent or a low dissolution rate pharmaceutical agent, wherein thepharmaceutical agent comprises greater than 11% by weight of the drugcomposition, wherein the solubilizing agent is a surfactant, and whereinthe surfactant comprises greater than about 10% by weight of the drugcomposition.

The present invention is further directed to a drug compositioncomprising a pharmaceautical agent and a solubilizing agent, wherein thepharmaceutical agent is selected from a low solubility pharmaceuticalagent or a low dissolution rate pharmaceutical agent, wherein thepharmaceutical agent comprises greater than 11% by weight of the drugcomposition and wherein the solubilizing agent is a surfactant.

In an embodiment of the present invention is a drug compositioncomprising a pharmaceutical agent, a solubilizing agent and a structuralpolymer, wherein the pharmaceutical agent is selected from a lowsolubility pharmaceutical agent or a low dissolution rate pharmaceuticalagent, and wherein the pharmaceutical agent comprises greater than 11%by weight of the drug composition.

The present invention is further directed to a drug compositioncomprising topiramate and a solubilizing agent. In an embodiment of thepresent invention, the topiramate comprises greater than 11% by weightof the drug composition. In another embodiment of the present inventionis a drug composition comprising topiramate, a solubilizing agent and astructural polymer. Preferably, the solubilizing agent is a surfactant.Preferably, the solubilizing agent comprises greater than about 10% byweight of the drug composition.

In an embodiment of the present invention is a drug compositioncomprising topiramate and a solubilizing agent, wherein the topiramatecomprises greater than 11% by weight of the drug composition, whereinthe solubilizing agent is a surfactant, and wherein the surfactantcomprises greater than about 10% by weight of the drug composition.

In an embodiment of the present invention is a drug composition, whereinthe pharmaceutical agent, preferably topiramate, comprises greater thanabout 20% by weight of the drug composition. Preferably, thepharmaceutical agent, preferably topiramate, comprises greater thanabout 30% by weight of the drug composition, more preferably, thepharmaceutical agent, preferably topiramate, comprises greater thanabout 40% by weight of the drug composition.

In another embodiment of the present invention is a drug composition,wherein the pharmaceutical agent, preferably topiramate, comprisesbetween about 25% and about 55% by weight of the drug composition.Preferably, the pharmaceutical agent, preferably topiramate, comprisesbetween about 30% and about 50% by weight of the drug composition.

In an embodiment of the present invention is a drug composition, whereinthe solubilizing agent is a surfactant. In another embodiment of thepresent invention is a drug composition, wherein the solubilizing agent,preferably surfactant, comprises about 10% by weight of the drugcomposition, preferably, about 20% by weight of the drug composition,more prefereably, about 30% by weight of the drug composition, mostpreferably, about 40% by weight of the drug composition.

In another embodiment of the present invention is a drug composition,wherein the solubilizing agent, preferably a surfactant, comprisesbetween about 35% and about 55% by weight of the drug composition.Preferably, the solubilizing agent, preferably surfactant, comprisesbetween about 40% and about 50% by weight of the drug composition.

In an embodiment fo the present invention, the solubilizing agent ispresent in an amount greater than about 5%, more preferably, in anamount greater than about 10%, more preferably still, in an amountgreater than about 17.5%, more preferably still, in an amount greaterthan about 25%, more preferably still, in an amount greater than about30%, more preferably still, in an amount greater than about 40%, morepreferably still, in an amount greater than about 42.5%, more preferablystill, in an amount greater than about 45%.

In another embodiment of the present invention is a drug compositionfurther comprising a structural polymer. Preferably, the structuralpolymer comprises between about 1% and about 90% by weight of the drugcomposition, preferably, the structural polymer comprises between about5% and about 75% by weight of the drug composition, more preferably, thestructural polymer comprises between about 10% and about 40% by weightof the drug composition.

The present invention is further directed to a dosage form comprisingany of the drug compositions or formulations described herein. In anembodiment of the present invention is a dosage form comprising a drugcomposition, wherein the drug composition comprises topiramate and asolubilizing agent.

In an embodiment of the present invention, the dosage form is a matrixform. In another embodiment of the present invention, the dosage form isan osmotic dosage form. In another embodiment of the present invention,the dosage form is a controlled release dosage form. Preferably, thedosage form is a controlled release, osmotic dosage form, preferably fororal administration.

In an embodiment of the present invention is a dosage form comprising adrug composition as described herein, wherein the pharmaceutical agentis present in an amount in the range of about 1 milligram to about 750milligrams, preferably about 5 milligrams to about 250 milligramns, morepreferably about 10 milligrams to about 250 milligrams. In anotherembodiment of the present invention is a dosage form comprising two drugcompositions as described herein, wherein the sum of the amount ofpharmaceutical agent present within the drug compositions is in therange of about 1 milligram to about 750 milligrams, preferably about 5milligrams to about 250 milligramns, more preferably about 10 milligramsto about 250 milligrams.

In another embodiment of the present invention is a dosage formcomprising a drug composition, wherein the drug composition comprisestopiramate, and a solubilizing agent, and wherein the topiramate ispresent in an amount in the range of about 1 milligram to about 750milligrams, preferably about 5 milligrams to about 250 milligrams, morepreferably about 10 milligrams to about 250 milligrams, more preferablystill, the topiramate is present in an amount selected from 10 mg, 20mg, 40 mg, 45 mg, 80 mg, 90 mg, 120 mg, 135 mg, 160 mg, 180 mg or 200mg.

In another embodiment of the present invention is a dosage formcomprising two drug compositions, wherein each drug compositioncomprises topiramate and an independently selected solubilizing agent,preferably surfactant, and wherein the sum of the amount of topiramatewith the drug compositions is in the range of about 1 milligram to about750 milligrams, preferably about 5 milligrams to about 250 milligramns,more preferably about 10 milligrams to about 250 milligrams, morepreferably still, the topiramate is present in an amount selected from10 mg, 20 mg, 40 mg, 45 mg, 80 mg, 90 mg, 120 mg, 135 mg, 160 mg, 180 mgor 200 mg.

In an embodiment of the present invention is a dosage form comprising(a) a core comprising a first drug composition and a push layercomprising an osmopolymer; (b) a semi-permeable wall surrounding thecore; and (c) an exit orifice through the semi-permeable wall forreleasing the drug compositions from the dosage form over a prolongedperiod of time.

In another embodiment of the present invention is a dosage formcomprising (a) a core comprising a first drug composition, a second drugcompsition and a push layer comprising an osmopolymer; (b) asemi-permeable wall surrounding the core; and (c) an exit orificethrough the semi-permeable wall for releasing the drug compositions fromthe dosage form over a prolonged period of time.

In another embodiment of the present invention is a dosage formcomprising (a) a core comprising a first drug composition, a second drugcompsition and a push layer, wherein the first and second drugcompsitition comprise topiramate and independently selected solubilizingagents; (b) a semi-permeable wall surrounding the core; and (c) an exitorifice through the semi-permeable wall for releasing the drugcompositions from the dosage form over a prolonged period of time.

In another embodiment of the present invention is a dosage formcomprising (a) a core comprising a first drug composition comprising apharmaceutical agent and a solubilizing agent wherein the pharmaceuticalagent is selected from a low solubility pharmaceutical agent or a lowdissolution rate pharmaceutical agent, preferably topiramate, whereinthe pharmaceutical agent comprises greater than 11% by weight of thedrug composition, wherein the solubilizing agent is a surfactant, andwherein the surfactant comprises greater than about 10% by weight of thedrug composition; a second drug composition comprising a pharmaceuticalagent and a solubilizing agent wherein the pharmaceutical agent isselected from a low solubility pharmaceutical agent or a low dissolutionrate pharmaceutical agent, wherein the pharmaceutical agent comprisesgreater than 11% by weight of the drug composition, wherein thesolubilizing agent is a surfactant, and wherein the surfactant comprisesgreater than about 10% by weight of the drug composition; and a pushlayer, (b) a semi-permeable wall surrounding the core; and (c) an exitorifice through the semi-permeable wall for releasing the drugcompositions from the dosage form over a prolonged period of time

In an embodiment of the present invention, the pharmaceutical agent andsolubilizing agent in the first and second drug compositions areindependently selected. Preferably, the pharmaceutical agent in thefirst and second drug compositions is the same, more preferably, thepharmaceutical agent in the first and second drug compositions istopiramate.

In an embodiment of the present invention, the amount and/orconcentration of the pharmaceutical agent, preferably topiramate, withinthe first drug composition is less than the amount and/or concentrationof the pharmaceutical agent, preferably topiramate, within the seconddrug composition.

In another embodiment of the present invention is a dosage formcomprising (a) a core comprising a first drug composition, a second drugcomposition and a push layer comprising an osmopolymer; (b) asemi-permeable wall surrounding the core; and (c) an exit orificethrough the semi-permeable wall for releasing the first drug compositionand the second drug composition from the dosage form over a prolongedperiod of time; wherein the first drug composition comprises betweenabout 25% and about 40% by weight of topiramate and between about 35%and about 50% by weight of a surfactant, and the second drug compositioncomprises between about 30% and about 40% by weight of topiramate andbetween about 45% and 55% by weight of a surfactant. In a preferredembodiment of the present invention, the first drug composition furthercomprises between about 10% and about 20% by weight of a structuralpolymer, and the second drug composition further comprises between about0% and about 10% by weight of a structural polymer. Preferably, thefirst drug composition comprises between about 30% and about 35% byweight of topiramate, between about 40% and about 45% by weight of thesurfactant, and between about 15% and about 20% by weight of thestructural polymer, and the second drug composition comprises betweenabout 40% and about 45% by weight of topiramate, between about 46% andabout 54% by weight of the surfactant, and between about 0% and about 5%by weight of the structural polymer. More preferably, the first drugcomposition comprises about 32% by weight of topiramate, about 42% byweight of the surfactant, and about 16% by weight of the structuralpolymer, and the second drug composition comprises about 43% by weightof topiramate, about 50% by weight of the surfactant, and about 0% byweight of the structural polymer. Preferably, the surfactant in both thefirst and second drug compositions is LUTROL F127 and the structuralpolymer in both the first and second drug compositions is POLYOX N80.

In another embodiment of the present invention is a dosage formcomprising (a) a core comprising a first drug composition, a second drugcomposition and a push layer comprising an osmopolymer; (b) asemi-permeable wall surrounding the core; and (c) an exit orificethrough the semi-permeable wall for releasing the first drug compositionand the second drug composition from the dosage form over a prolongedperiod of time; wherein the first drug composition comprises betweenabout 1% and about 25% by weight of topiramate and between about 1% and35% by weight of a surfactant, and the second drug composition comprisesbetween about 10% and about 25% by weight of topiramate and betweenabout 10% and 35% by weight of a surfactant. In a preferred embodimentof the present invention, the first drug composition further comprisesbetween about 75% and about 95% by weight of a structural polymer, andthe second drug composition further comprises between about 65% andabout 80% by weight of a structural polymer. Preferably, the first drugcomposition comprises between about 2% and about 8% by weight oftopiramate, between about 1% and about 5% by weight of the surfactant,and between about 85% and about 90% by weight of the structural polymer,and the second drug composition comprises between about 10% and about15% by weight of topiramate, between about 10% and about 15% by weightof the surfactant, and between about 70% and about 75% by weight of thestructural polymer. More preferably, the first drug compositioncomprises about 5% by weight of topiramate, about 2% by weight of thesurfactant, and about 89% by weight of the structural polymer, and thesecond drug composition comprises about 12% by weight of topiramate,about 12% by weight of the surfactant, and about 72% by weight of thestructural polymer. Preferably, the surfactant in both the first andsecond drug compositions is LUTROL F127 and the structural polymer inboth the first and second drug compositions is POLYOX N80.

In an embodiment of the present invention, the push layer comprises anosmopolymer. In another embodiment of the present invention, the pushlayer comprises an osmopolymer and an osmoagent.

In an embodiment of the present invention, the dosage form releases drugover a prolonged period of time, preferably over greater than 4 hours,more preferably, over greater than about 8 hours, more preferably still,over greater than about 10 hours, most preferably, over greater thanabout 14 hours. In another embodiment of the present invention, thedosage form releases drug over a prolonged period of time greater thanabout 14 hours and up to about 24 hours.

In an embodiment of the present invention, the dosage form releases drugwith a substantially ascending rate of release. In another embodiment ofthe present invention, the dosage form releases drug with asubstantially ascending rate of release. In yet another embodiment ofthe present invention, the dosage form releases drug at a rate whichresults in a substantially ascending drug plasma concentration.

In an embodiment of the present is a drug composition comprisingtopiramate, a surfactant, preferably LUTROL F127 and a structuralpolymer, preferably POLYOX N80; wherein the topiramate comprises about5% by weight of the drug composition, wherein the surfactant comprisesabout 2% by weight of the drug composition, and wherein the structuralpolymer comprises about 88.7% by weight of the drug composition.

In an embodiment of the present is a drug composition comprisingtopiramate, a surfactant, preferably LUTROL F127 and a structuralpolymer, preferably POLYOX N80; wherein the topiramate comprises about12% by weight of the drug composition, wherein the surfactant comprisesabout 12% by weight of the drug composition, and wherein the structuralpolymer comprises about 71.7% by weight of the drug composition.

In an embodiment of the present is a drug composition comprisingtopiramate, a surfactant, preferably LUTROL F127 and a structuralpolymer, preferably POLYOX N80; wherein the topiramate comprises about32% by weight of the drug composition, wherein the surfactant comprisesabout 42% by weight of the drug composition, and wherein the structuralpolymer comprises about 16.5% by weight of the drug composition.

In an embodiment of the present is a drug composition comprisingtopiramate, and a surfactant, preferably LUTROL F127; wherein thetopiramate comprises about 43% by weight of the drug composition, andwherein the surfactant comprises about 49.9% by weight of the drugcomposition.

In an embodiment of the present invention is a drug compositioncomprising topiramate, wherein the topiramate comprises about 5% byweight of the drug composition; surfactant, preferably LUTROL F127wherein the surfactant comprises about 2% by weight of the drugcomposition; a structural polymer, preferably POLYOX N80 wherein thestructural polymer comprises about 88.7% by weight of the drugcomposition; PVP, preferably PVP K29-32, wherein the PVP comprises about3% by weight of the drug composition; stearic acid, wherein the stearicacid comprises about 1% by weight of the drug composition; magnesiumstearate, wherein the magnesium stearate comprises about 0.25% by weightof the drug composition; and butylated hydroxytoluene (BHT), wherein theBHT comprises about 0.02% by weight of the drug composition.

In an embodiment of the present invention is a drug compositioncomprising topiramate, wherein the topiramate comprises about 12% byweight of the drug composition; surfactant, preferably LUTROL F127,wherein the surfactant comprises about 12% by weight of the drugcomposition; a structural polymer, preferably POLYOX N80, wherein thestructural polymer comprises about 71.7% by weight of the drugcomposition; PVP, preferably PVP K29-32, wherein the PVP comprises about3% by weight of the drug composition; stearic acid, wherein the stearicacid comprises about 1% by weight of the drug composition; magnesiumstearate, wherein the magnesium stearate comprises about 0.25% by weightof the drug composition; iron oxide, wherein the iron oxide comprisesabout 0.02% by weight of the drug composition, and BHT, wherein the BHTcomprises about 0.02% by weight of the drug composition.

In an embodiment of the present invention is a drug compositioncomprising topiramate, wherein the topiramate comprises about 32% byweight of the drug composition; surfactant, preferably LUTROL F127,wherein the surfactant comprises about 42% by weight of the drugcomposition; a structural polymer, preferably POLYOX N80, wherein thestructural polymer comprises about 16.5% by weight of the drugcomposition; PVP, preferably PVP K29-32, wherein the PVP comprises about3% by weight of the drug composition; stearic acid, wherein the stearicacid comprises about 1% by weight of the drug composition; magnesiumstearate, wherein the magnesium stearate comprises about 0.5% by weightof the drug composition; BHT, wherein the BHT comprises about 0.02% byweight of the drug composition and methylcellulose, wherein themethylcellulose comprises about 2.5% by weight of the drug composition.

In an embodiment of the present invention is a drug compositioncomprising topiramate, wherein the topiramate comprises about 43% byweight of the drug composition; surfactant, preferably LURTOL F127,wherein the surfactant comprises about 49.9% by weight of the drugcomposition; PVP, preferably PVP K29-32, wherein the PVP comprises about3% by weight of the drug composition; stearic acid, wherein the stearicacid comprises about 1% by weight of the drug composition; magnesiumstearate, wherein the magnesium stearate comprises about 0.5% by weightof the drug composition; ferric oxide, wherein the ferric oxidecomprises about 0.08% by weight of the drug composition; BHT, whereinthe BHT comprises about 0.02% by weight of the drug composition andmethylcellulose, wherein the methylcellulose comprises about 2.5% byweight of the drug composition.

In an embodiment of the present invention is a dosage form comprising(a) a core comprising a first drug composition comprising topiramate, asurfactant, preferably LUTROL F127 and a structural polymer, preferablyPOLYOX N80 wherein the topiramate comprises about 5% by weight of thedrug composition, wherein the surfactant comprises about 2% by weight ofthe drug composition, and wherein the structural polymer comprises about88.7% by weight of the drug composition; a second drug compositioncomprising topiramate, a surfactant, preferably LUTROL F127 and astructural polymer, preferably POLYOX N80 wherein the topiramatecomprises about 12% by weight of the drug composition, wherein thesurfactant comprises about 12% by weight of the drug composition, andwherein the structural polymer comprises about 71.7% by weight of thedrug composition; and a push layer.

In another embodiment of the present invention is a dosage formcomprising (a) a core comprising a first drug composition comprisingtopiramate, a surfactant, preferably LUTROL F127 and a structuralpolymer, preferably POLYOX N80; wherein the topiramate comprises about32% by weight of the drug composition, wherein the surfactant comprisesabout 42% by weight of the drug composition, and wherein the structuralpolymer comprises about 16.5% by weight of the drug composition; asecond drug composition comprising topiramate, and a surfactant,preferably LUTROL F127; wherein the topiramate comprises about 43% byweight of the drug composition, and wherein the surfactant comprisesabout 49.9% by weight of the drug composition; and a push layer.

In an embodiment of the present invention is a dosage form comprising(a) a core comprising a first drug composition comprising topiramate,wherein the topiramate comprises about 5% by weight of the drugcomposition; surfactant, preferably LUTROL F127 wherein the surfactantcomprises about 2% by weight of the drug composition; a structuralpolymer, preferably POLYOX N80, wherein the structural polymer comprisesabout 88.7% by weight of the drug composition; PVP, preferably PVPK29-32, wherein the PVP comprises about 3% by weight of the drugcomposition; stearic acid, wherein the stearic acid comprises about 1%by weight of the drug composition; magnesium stearate, wherein themagnesium stearate comprises about 0.25% by weight of the drugcomposition; and BHT, wherein the BHT comprises about 0.02% by weight ofthe drug composition; a second drug composition comprising topiramate,wherein the topiramate comprises about 12% by weight of the drugcomposition; surfactant, preferably LUTROL F127 wherein the surfactantcomprises about 12% by weight of the drug composition; a structuralpolymer, preferably POLYOX N80, wherein the structural polymer comprisesabout 71.7% by weight of the drug composition; PVP, preferably PVPK29-32, wherein the PVP comprises about 3% by weight of the drugcomposition; stearic acid, wherein the stearic acid comprises about 1%by weight of the drug composition; magnesium stearate, wherein themagnesium stearate comprises about 0.25% by weight of the drugcomposition; iron oxide, wherein the iron oxide comprises about 0.02% byweight of the drug composition, and BHT, wherein the BHT comprises about0.02% by weight of the drug composition; and a push layer comprising anosmopolymer; (b) a semi-permeable wall surrounding said core; and (c) anexit orifice through the semi-permeable wall for releasing the firstdrug composition and the second drug composition from the dosage formover a prolonged period of time.

In another embodiment of the present invention is a dosage formcomprising (a) a core comprising a first drug composition comprisingtopiramate, wherein the topiramate comprises about 32% by weight of thedrug composition; surfactant, preferably LUTROL F127, wherein thesurfactant comprises about 42% by weight of the drug composition; astructural polymer, preferably POLYOX N80, wherein the structuralpolymer comprises about 16.5% by weight of the drug composition; PVP,preferably PVP K29-32, wherein the PVP comprises about 3% by weight ofthe drug composition; stearic acid, wherein the stearic acid comprisesabout 1% by weight of the drug composition; magnesium stearate, whereinthe magnesium stearate comprises about 0.5% by weight of the drugcomposition; BHT, wherein the BHT comprises about 0.02% by weight of thedrug composition and methylcellulose, wherein the methylcellulosecomprises about 2.5% by weight of the drug composition; a second drugcomposition comprising topiramate, wherein the topiramate comprisesabout 43% by weight of the drug composition; surfactant, preferablyLUTROL F127, wherein the surfactant comprises about 49.9% by weight ofthe drug composition; PVP, preferably PVP K29-32, wherein the PVPcomprises about 3% by weight of the drug composition; stearic acid,wherein the stearic acid comprises about 1% by weight of the drugcomposition; magnesium stearate, wherein the magnesium stearatecomprises about 0.5% by weight of the drug composition; ferric oxide,wherein the ferric oxide comprises about 0.08% by weight of the drugcomposition; BHT, wherein the BHT comprises about 0.02% by weight of thedrug composition and methylcellulose, wherein the methylcellulosecomprises about 2.5% by weight of the drug composition; and a push layercomprising an osmopolymer; (b) a semi-permeable wall surrounding saidcore; and (c) an exit orifice through the semi-permeable wall forreleasing the first drug composition and the second drug compositionfrom the dosage form over a prolonged period of time.

In an embodiment of the present invention is a method of treating adisorder selected from the group consisting of epilepsy, migraine,glaucoma and other ocular disorders (including diabetic retinopathy),essential tremor, restless limb syndrome, obesity, weight loss, Type IIDiabetes Mellitus, Syndrome X, impaired oral glucose tolerance, diabeticskin lesions, cluster headaches, neuralgia, neuropathic pain (includingdiabetic neuropathy), elevated blood glucose levels, elevated bloodpressure, elevated lipids, bipolar disorder, dementia, depression,psychosis, mania, anxiety, schizophrenia, OCD, PTSD, ADHD, impulsecontrol disorders (including bulimia, binge eating, substance abuse,etc.), ALS, asthma, autism, autoimmune disorders (including psoriasis,rheumatoid arthritis, etc.), chronic neurodegenerative disorders, acuteneurodegeneration, sleep apnea and other sleep disorders and/or forpromoting wound healing, comprising administering to a subject in needthereof, of any of the drug compositions or dosage forms describedherein.

Preferably, the disorder is selected from the group consisting ofepilepsy, migraine, diabetic retinopathy, diabetic neuropathy, diabeticskin lesions, obesity, weight loss, Type II Diabetes Mellitus, SyndromeX, impaired oral glucose tolerance, elevated blood glucose levels andelevated blood pressure.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows smearing of a formulation compressed in the absence ofcoated granules.

The following six figures (FIGS. 2 to 7) are not drawn to scale, and areset forth to illustrate various embodiments of the invention.

FIG. 2 illustrates an embodiment of an osmotic dosage form of thepresent invention, illustrating the dosage form prior to administrationto a subject.

FIG. 3 illustrates the dosage form of FIG. 2 in opened section,illustrating a single internally housed drug composition.

FIG. 4 illustrates the dosage form of FIG. 2 in opened section view,illustrating a bi-layer comprising a drug composition and a separate andcontacting push layer for pushing the drug composition from the dosageform.

FIG. 5 illustrates the dosage form of FIG. 2, which further comprises animmediate release external overcoat of pharmaceutical agent on thedosage form.

FIG. 6 illustrates an opened view of another embodiment of the dosageform of the present invention illustrating a tri-layer arrangementcomprising two drug compositions in parallel arrangement and a separateand contacting push layer for pushing the drug layers from the capsuleshaped dosage form.

FIG. 7 shows release of drug from a controlled release dosage formconsisting of a push-stick system with coated granules.

FIG. 8 shows topiramate release patterns of control release topiramatedosage forms having coated granules in a 1 kg (upper panel) and 30 kg(lower panel) batch size.

FIG. 9 shows the topiramate release from control release topiramatedosage forms. In all dosage forms, the granules were coated with 23%PVP. Top panel: 0% methylcellulose granule coating; bottom panel: 3%methylcellulose granule coating.

FIG. 10 shows delivery patterns of topiramate dosage forms as a functionof the LUTROL F127/topiramate (surfactant/drug) weight ratios in thecoated granules. From top to bottom panels: 1.86 surfactant/drug; 1.49surfactant/drug; 1.18 surfactant/drug; 0.93 surfactant/drug.

FIG. 11 shows delivery patterns of topiramate dosage forms as a functionof coating content. Top panel: 23% PVP with 3% methylcellulose bilayercoating; bottom panel 10% POLYOX N10 single layer coating.

FIG. 12 shows smear resistance and delivery patterns of topiramatedosage forms as a function of coating thickness. Top to bottom panels:3% methylcellulose; 7% methylcellulose; 13% methylcellulose.

FIG. 13 shows smear resistance and delivery patterns of topiramatedosage forms as a function of coating content. Top panel: single layer,3% methylcellulose; bottom panel: bilayer, 10% PVP with 3%methylcellulose granule coating.

FIG. 14 shows delivery patterns of topiramate dosage forms as a functionof coating content. All dosage form coatings have 10% PVP. Top to bottompanels: 3% methylcellulose; 7% methylcellulose; 10% methylcellulosegranule coating.

DETAILED DESCRIPTION OF THE INVENTION Terminology

The present invention is best understood by reference to the followingdefinitions, the drawings and exemplary disclosure provided herein.

To provide a more concise description, some of the quantitativeexpressions given herein are not qualified with the term “about”. It isunderstood that whether the term “about” is used explicityly or not,every quantity given herein is meant to refer to the actual given value,and it is also meant to refer to the approximation to such given valuethat would reasonably be inferred based on the ordinary skill in theart, including approximations due to the experimental and/or measurementconditions for such given value.

The expressions “exit”, “exit orifice” and “delivery port” shall mean anopening in a dosage form which permits drug to exit the dosage form.Suitable examples include, but are not limited to, a passageway; anaperture; an orifice; and a bore. The expressions also include anorifice that is formed or formable from a substance or polymer thaterodes, dissolves or is leached from the outer wall to thereby form anexit orifice.

By “dosage form” is meant a pharmaceutical composition or device capableof delivering a pharmaceutical agent. Suitable examples of dosage formsinclude, but are not limited to tablets, capsules, gel-caps, matrixforms, osmotic forms, immediate release forms, controlled release forms,sustained release forms, extended release forms, and the like.Similarly, the term “tablet core” shall mean any drug composition orformulation which comprises that portion of the dosage form whichcomprises the therapeutic or pharmaceutical agent. The tablet core maybe incoprprated into any suitable dosage form, including, but notlimited to a tablet, capsule, gel cap, and the like. Further, the tabletcore may optionally be surrounded, partially or completely, by an outerlayer, for example a semi-permeable membrane wall, hard shell capsule,and the like. The tablet core may be further optionally compressed orconstituted by filling or the like.

As used herein, unless otherwise noted, the terms “drug composition” and“drug formulation” shall mean a formulation comprising at least onepharmaceutical agent. Preferably, the drug composition comprises apharmaceutical agent and a solubilizing agent, preferably, a surfactant,more preferably a solubilizing surfactant. More preferably, the drugcomposition comprises a pharmaceutical agent, a solubilizing agent,preferably, a surfactant and a structural polymer. The drug compositionmay further optionally contain one or more inactive ingredients, i.e.,pharmaceutically acceptable excipients such as disintegrants, binders,diluents, lubricants, stabilizers, antioxidants, osmotic agents,colorants, plasticizers, coatings and the like.

As used herein, unless otherwise noted, the term “push layer” shall meana formulation which does not contain pharmaceutical agent and whichcomprises an osmopolymer. Preferably, the push layer comprises anosmopolymer and an osmoagent. The push layer may further optionallycontain one or more inactive ingredients, for example disintegrants,binders, diluents, lubricants, stabilizers, antioxidants, osmoticagents, colorants, plasticizers, coatings and the like. Similarly, theterm “osmotic delivery system” shall mean any means for delivering atherapeutic or pharmaceutical agent which uses osmotic gradient toachieve such delivery, for example a push layer as described above.

As used herein, unless otherwise noted, the terms “pharmaceuticalagent”, “therapeutic drug”, “therapeutic agent”, “drug compound” and“drug” shall mean a pharmaceutical agent, drug, compound,pharmaceutically acceptable salt, prodrug or derivative thereof.Preferably, the pharmaceutical agent or drug is a low solubility and/orlow dissolution rate pharmaceutical agent. More preferably, thepharmaceutical agent is topiramate.

As used herein, unless otherwise noted, the term “pharmaceuticallyacceptable salt”, shall mean any salt whose anion or cation does notcontribute significantly to the toxicity or pharmacological activity ofthe salt, and, as such, they are the pharmacological equivalents of theacids or bases of the compound. Suitable pharmaceutically acceptablesalts include acid addition salts which may, for example, be formed byreacting the drug compound with a suitable pharmaceutically acceptableacid such as hydrochloric acid, sulfuric acid, fumaric acid, maleicacid, succinic acid, acetic acid, benzoic acid, citric acid, tartaricacid, carbonic acid or phosphoric acid; and base addition salts,including alkali metal salts, e.g., sodium or potassium salts; alkalineearth metal salts, e.g., calcium or magnesium salts; and salts formedwith suitable organic ligands, e.g., quaternary ammonium salts, whichmay be similarly prepared by reacting the drug compound with a suitablepharmaceutically acceptable base.

Thus, representative pharmaceutically acceptable salts include, but arenot limited to, the following: acetate, benzenesulfonate, benzoate,bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate,camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride,edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate,glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine,hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate,lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate,methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate,N-methylglucamine ammonium salt, oleate, pamoate (embonate), palmitate,pantothenate, phosphate/diphosphate, polygalacturonate, salicylate,stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate,tosylate, triethiodide and valerate.

Representative acids and bases which may be used in the preparation ofpharmaceutically acceptable salts include the following: acids includingacetic acid, 2,2-dichloroactic acid, acylated amino acids, adipic acid,alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid,benzoic acid, 4-acetamidobenzoic acid, (+)-camphoric acid,camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, capric acid,caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid,dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid,2-hydrocy-ethanesulfonic acid, formic acid, fumaric acid, galactaricacid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucoronicacid, L-glutamic acid, α-oxo-glutaric acid, glycolic acid, hipuric acid,hydrobromic acid, hydrochloric acid, (+)-L-lactic acid, (±)-DL-lacticacid, lactobionic acid, maleic acid, (−)-L-malic acid, malonic acid,(±)-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid,naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotincacid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitric acid,pamoic acid, phosphoric acid, L-pyroglutamic acid, salicylic acid,4-amino-salicylic acid, sebaic acid, stearic acid, succinic acid,sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid,p-toluenesulfonic acid and undecylenic acid; and bases includingammonia, L-arginine, benethamine, benzathine, calcium hydroxide,choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)-ethanol,ethanolamine, ethylenediamine, N-methyl-glucamine, hydrabamine,1H-imidazole, L-lysine, magnesium hydroxide,4-(2-hydroxyethyl)-morpholine, piperazine, potassium hydroxide,1-(2-hydroxyethyl)-pyrrolidine, secondary amine, sodium hydroxide,triethanolamine, tromethamine and zinc hydroxide.

As used herein the term “low solubility” shall mean that the neatpharmaceutical agent (in the absence of surfactants or other excipients)exhibits a solubility of less than about 100 mg/ml in de-ionized waterat 37° C. Preferably, low solubility shall mean a solubility of lessthan about 50 mg/ml, more preferably, less than about 25 mg/ml, morepreferably still, less than about 15 mg/ml, more preferably still, lessthan about 10 mg/ml, more preferably still, less than about 5 mg/ml,most preferably, less than about 1 mg/ml. Similarly, the term “lowlysoluble” when used to characterize a drug shall therefore mean a drugthat exhibits low solubility as herein defined.

As defined herein, the solubility of a pharmaceutical agent isdetermined by adding the pharmaceutical agent to stirred or agitatedde-ionized water maintained in a constant temperature bath at atemperature of 37° C. until no more pharmaceutical agent dissolves. Theresulting solution saturated with the pharmaceutical agent is thenfiltered, typically under pressure through a 0.8-micron Milliporefilter, and the concentration of the pharmaceutical agent in thesolution is measured by any appropriate analytical method includinggravimetric, ultraviolet spectrophometry, chromatography, and the like.The solubility of the pharmaceutical agent is measured at equilibrium.

As used herein, the term “low dissolution rate” shall mean that rate ofdissolution of the pharmaceutical agent under constant surface area (i.ethe rate at which the pharmaceutical agent dissolves in de-ionized waterat 37° C.) is between 0 mg/min/cm² and about 20 mg/min/cm², preferably,between about 0.1 mg/min/cm² and about 10 mg/min/cm², more preferably,between about 0.1 mg/min/cm² and about 5 mg/min/cm², more preferablystill, between about 0.1 mg/min/cm² and about 2 mg/min/cm², morepreferably still, between about 0.1 mg/min/cm² and about 1.5 mg/min/cm²,most preferably, between about 0.1 mg/min/cm² and about 1.25 mg/min/cm².

As defined herein, the dissolution rate of a pharmaceutical agent isdetermined by the method as described in USP 26, NF21, p.2333.

Suitable examples of low solubility pharmaceutical agents (i.e. thosewith a solubility in de-ionized water at 37° C. of less than about 100mg/ml) include, but are not limited to itraconazole, loratadine,thioridazine, thiethylperazine, ketoconazole, terfenadine, tretinoin,methdilazine, buprenorphine, thiothixene, simvastatin, indomethacin,domperidone, erythromycin, vitamin B, levonorgestrel, lovastatin,nicardipine, diclofenac, chlorpromazine, estradiol, digitoxin,liothyronine, glyburide, droperidol, verapamil, triazolam, fluocinonide,loxapine, prazepam, lindane, flurbiprofen, oxaprozin, progesterone,pimozide, methyclothiazide, ethinyl estradiol, finasteride, clozapine,haloperidol, diflunisal, prochloperazine, warfarin, imipramine,felodipine, mefenamic acid, methotrimeprazine, ibuprofen,spironolactone, nimodipine, biperiden, perphenazine, fluphenazine,methyltestosterone, glipizide, disopyramide, methoxsalen, diazepam,penicillin, ketoprofen, nifedipine, etoposide, metolazone, digoxin,betamethasone, fluoxymesterone, nabumetone, reserpine, furosemide,sulfadiazine, nitrendipine, nitrofurantoin, lorazepam, triamcinolone,omeprazole, dexamethasone, doxorubicin, clonazepam, bendroflumethiazide,chlorthalidone, methylprednisolone, pyrimethamine, flumazenil,tetracaine, fludrocortisone, quinidine, morphine, temazepam, oxazepam,epinephrine, fentanyl, cefazolin, prednisolone, tetracycline,chlorpropamide, chlorothiazide, azathioprine, prednisone,hydrocortisone, nystatin, phenazopyridine, trimethoprim, fenfluramine,isosorbide dinitrate, allopurinol, sulfamethoxazole, doxycycline,hydrochlorothiazide, amphotericin B, diphenoxylate, trichlormethiazide,zidovudine, famotidine, and the like.

Preferably, the low solubility pharmaceutical agent is other than (isnot) phenytoin. Preferably, the low solubility pharmaceutical agent isother than phenytoin and carbamazepine. Preferably, the low solubilitypharmaceutical agent is other than phenytoin, mephenytoin,phenobarbital, primidone, carbamazepine, ethosuximide, methsuximide,phensuximide, trimethadione, clonazipam, clorazepate, phenacemide,paramethadione, primaclone, clobazam, felbamate, flunarizine,lamotrigine, progabide, vibabatim, eterobarb, gabapentin, oxcarbazepine,ralitoline, tiagobine, sulthiame and tioridone.

The low solubility and/or low dissolution rate pharmaceutical agents maybe incorporated into the drug composition and/or dosage forms of thepresent invention in amounts in the range of from about 1 milligram toabout 750 milligrams, preferably in the range of from about 5 mg toabout 250 mg, more preferably in the range of from about 10 mg to about250 mg.

An “immediate-release dosage form” refers to a dosage form that releasesgreater than or equal to about 80% of the pharmaceutical agent in lessthan or equal to about 1 hour.

By “sustained release” is meant continuous release of a pharmaceuticalagent over a prolonged period of time.

By “controlled release” is meant continuous release of a pharmaceuticalagent over a prolonged period of time, wherein the pharmaceutical agentis released at a controlled rate over a controlled period of time.

By “prolonged period of time” is meant a continuous period of time ofgreater than about 1 hour, preferably, greater than about 4 hours, morepreferably, greater than about 8 hours, more preferably greater thanabout 10 hours, more preferably still, greater than about 14 hours, mostpreferably, greater than about 14 hours and up to about 24 hours.

As used herein, unless otherwise noted, “rate of release” or “releaserate” of a drug refers to the quantity of drug released from a dosageform per unit time, e.g., milligrams of drug released per hour (mg/hr).Drug release rates for dosage forms are typically measured as an invitro rate of drug release, i.e., a quantity of drug released from thedosage form per unit time measured under appropriate conditions and in asuitable fluid.

The release rates referred to herein are determined by placing a dosageform to be tested in de-ionized water in metal coil or metal cage sampleholders attached to a USP Type VII bath indexer in a constanttemperature water bath at 37° C. Aliquots of the release rate solutions,collected at pre-set intervals, are then injected into a chromatographicsystem fitted with an ultraviolet or refractive index detector toquantify the amounts of drug released during the testing intervals. Theabove described method is therefore an example of an in vitro releaserate assay.

As used herein a drug release rate obtained at a specified time refersto the in vitro release rate obtained at the specified time followingimplementation of the release rate test. The time at which a specifiedpercentage of the drug within a dosage form has been released from saiddosage form is referred to as the “T_(x)” value, where “x” is thepercent of drug that has been released. For example, a commonly usedreference measurement for evaluating drug release from dosage forms isthe time at which 70% of drug within the dosage form has been released.This measurement is referred to as the “T₇₀” for the dosage form.Preferably, T₇₀ is greater than or equal to about 8 hours, morepreferably, T₇₀ is greater than or equal to about 12 hours, morepreferably still, T₇₀ is greater than to equal to about 16 hours, mostpreferably, T₇₀ is greater than or equal to about 20 hours. Preferably,T₇₀ is less than about 24 hours, more preferably, T₇₀ is less than about20 hours.

By “C” is meant the concentration of drug in blood plasma, or serum, ofa subject, generally expressed as mass per unit volume, typicallynanograms per milliliter. For convenience, this concentration may bereferred to herein as “drug plasma concentration”, “plasma drugconcentration” or “plasma concentration” which is intended to beinclusive of a drug concentration measured in any appropriate body fluidor tissue. The plasma drug concentration at any time following drugadministration is referenced as C_(time), as in C_(9h) or C_(24h), etc.

As used herein, “steady state” when used in describing the drug plasmaconcentration of a pharmaceutical agent, shall mean a plasma drugconcentration in the range of from about 5 ng/ml to about 500 ng/ml,preferably, from about 25 ng/ml to about 250 ng/ml, with the provisothat during the 24 hour period after administration the quotient formedby [C_(max)−C_(min)]/C_(avg) (i.e. the variation in the blood plasmaconcentration of the drug) is about 3 or less, preferably, about 2 orless, more preferably, about 1 or less.

Persons of skill in the art will appreciate that blood plasma drugconcentrations obtained in individual subjects will vary due tointerpatient variability in the many parameters affecting drugabsorption, distribution, metabolism and excretion. For this reason,unless otherwise indicated, when a drug plasma concentration is listed,the value listed is the calculated mean value based on values obtainedfrom a groups of subjects tested.

As used herein, unless otherwise noted, the term “zero order rate ofrelease” shall mean a rate of release wherein the amount of drugreleased as a function of time is substantially constant. Moreparticularly, the rate of release of drug as a function of time shallvary by less than about 30%, preferably, less than about 20%, morepreferably, less than about 10%, most preferably, less than about 5%,wherein the measurement is taken over the period of time wherein thecumulative release is between about 25% and about 75%, preferably,between about 25% and about 90%.

As used herein unless otherwise noted, the term “ascending rate ofrelease” shall mean a rate of release wherein the amount of drugreleased as a function of time increases over a period of time,preferably continuously and gradually. Preferably, the rate of drugreleased as a function of time increases in a steady (rather thanstep-wise) manner. More preferably, an ascending rate of release may becharacterized as follows. The rate of release as a function of time fora dosage form is measured and plotted as % drug release versus time oras milligrams of drug released/hour versus time. An ascending rate ofrelease is characterized by an average rate (expressed in mg of drug perhour) wherein the rate within a given two hour span is higher ascompared with the previous two hour time span, over the period of timeof about 2 hours to about 12 hours, preferably, about 2 hours to about18 hours, more preferably about 4 hours to about 12 hours, morepreferably still, about 4 hours to about 18 hours. Preferably, theincrease in average rate is gradual such that less than about 30% of thedose is delivered during any 2 hour interval, more preferably, less thanabout 25% of the dose is delivered during any 2 hour interval.Preferably, the ascending release rate is maintained until at leastabout 50%, more preferably until at least about 75% of the drug in thedosage form has been released.

One skilled in the art will recognize that as the increase in the areaunder the curve increases (e.g from 1% to 10%), the total time overwhich the drug is released from the dosage form will necessarilydecrease and as such the determination of ascending rate of release willspan a shorter overall period of time.

As used herein, the term or “ascending drug plasma concentration” shallmean a drug plasma concentration profile over about the first 24 hoursfollowing initial dosing, wherein the profile shows an increase to amaximum concentration, wherein said maximum occurs more than about 6hours following the initial dose, preferably, more than about 8 hoursfollowing initial dose, more preferably, more than about 12 hours afterdose.

When referring to a drug composition, “high dosage” shall mean a drugcomposition wherein the pharmaceutical agent, preferably topiramate, ispresent in an amount greater than or equal to about 20%, preferablygreater than or equal to about 30%, more preferably greater than orequal to about 40%, by weight of the total drug composition.

When referring to a dosage form, “high dosage” shall mean a dosage formwherein the pharmaceutical agent, preferably topiramate, is present inan amount greater than or equal to about 20%, preferably greater than orequal to about 30%, more preferably greater than or equal to about 40%,by weight of the drug compositions within the dosage form.

As used herein, the term “therapeutically effective amount” shall meanthat amount of pharmaceutical agent that elicits the biological ormedicinal response in a tissue system, animal or human that is beingsought by a researcher, veterinarian, medical doctor or other clinician,which includes alleviation of the symptoms of the disease or disorderbeing treated.

The term “subject” as used herein, refers to an animal, preferably, amammal, most preferably, a human, who has been the object of treatment,observation or experiment.

As used herein, unless otherwise noted, the term “structural polymer”shall mean any component, for example a polymer or sugar, which iscapable of water absorption and which may increase the viscosity of thedrug compositions and/or may impart osmotic activity to the drugcomposition and or may act as a suspending agent for the drugcomposition. Suitable examples of structural polymers include, but arenot limited to poly(alkyleneoxide polymers of between 100,000 and750,000 molecular weight, including polyethylene oxide (such as POLYOX®N80; POLYOX®N10, POLYOX N750, and the like); polymethylene oxide,polybutylene oxide and polyhexylene oxide, andpoly(carboxymethylcellulose) of 40,000 to 400,000 number averagemolecular weight, represented by poly(alkali carboxymethylcellulose),poly(sodium carboxymethylcellulose), poly(potassiumcarboxymethylcellulose), poly(litihium carboxymethylcellulose), and thelike. Suitable example also include, but are not limited to sugars suchas maltrodextrins (such as MALTRIN M040, MALTRIN M100, MALTRIN M150,MALTRIN M200, MALTRIN M250, and the like); sugars comprising lactose,glucose, raffinose, sucrose, mannitol, sorbitol and the like. Suitableexamples also include, but are not limited to polyvinylpyrrolidone (PVP)(such as PVPs of grades 12PF or K2932, and the like);hydroxypropylcellulose; hydroxy propyl alkylcellulose of 9200 to 125,000average molecular weight represented by hydroxypropyl ethylcellulose,hydroxypropoyl methylcellulose, hydroxypropyl butylcellu lose,hydroxypropyl pentylcellulose, and the like; polyvinyl pyrrolisone vinylacetate co-olymers; and poly(vinylpyrrolidone) of upto 1,000,000 averagemolecular weight. Preferably, the structural polymer is apolyethyleneoxide polymers of between 100,000 and 300,000 molecularweight. More preferably, the structural polymer is POLYOX®N80.

Preferably, the structural polymer is selected from MALTRIN M100, POLYOXN10 and POLYOX N80, more preferably, the structural polymer is POLYOXN80.

As used herein, unless otherwise noted, the term “solubilizing agent”shall mean any component which increases the solubility and/ordissolution rate of a pharmaceutical agent. Preferably, the solubilizingagent is a surfactant. Suitable examples of solubilizing agents include,but are not limited to polyethylene glycol (PEG) 3350, polyethyleneglycol 8K, and surfactants including, but not limited to, KOLLIDON K90,KOLLIDON 12PF, KOLLIDON 17PF, KOLLIDON 25/30; LUTROL F68, LUTROL F87,LUTROL F127, LUTROL F108; MYRJ 52, MYRJ 53; PVP K2939, and the like.Additional preferred surfactants include, but are not limited to,sorbitan monopalmitate, sorbitan monostearate, glycerol monostearate,polyoxyethlene stearate, sucrose cocoate, polyoxyethylene 40 sorbitollanolin derivative, polyoxyethylene 75 sorbitol lanolin derivative,polyoxyethylene 6 sorbitol beeswax derivative, polyoxyethylene 20sorbitol beeswax derivative, polyoxyethylene 20 sorbitol lanolinderivative, polyoxyethylene 50 sorbitol lanolin derivative,polyoxyethylene 23 lauryl ether, polyoxyethylene 23 lauryl ether withbutylated hydroxyanisole and citric acid added as preservatives,polyoxyethylene 2 cetyl ether with butylated hydroxyanisole and citricacid added as preservatives, polyoxyethylene 2 stearyl ether,polyoxyethylene 21 stearyl ether, polyoxyethylene 100 stearyl ether,polyoxyethylene 10 cetyl ether with butylated hydroxyanisole and citricacid added as preservatives, polyoxyethylene 20 cetyl ether withbutylated hydroxyanisole and citric acid added as preservatives,polyoxyethylene 2 stearyl ether with butylated hydroxyanisole and citricacid added as preservatives, polyoxyethylene 10 stearyl ether withbutylated hydroxyanisole and citric acid added as preservatives,polyoxyethylene 20 stearyl ether with butylated hydroxyanisole andcitric acid added as preservatives, polyoxyethylene 21 stearyl etherwith butylated hydroxyanisole and citric acid added as preservatives,polyoxyethylene 20 oleyl ether with butylated hydroxyanisole and citricacid added as preservatives, polyoxyethylene 40 stearate,polyoxyethylene 50 stearate, polyoxyethylene 100 stearate, sorbitanmonopalmitate, sorbitan monostearate, sorbitan tristearate,polyoxyethylene 4 sorbitan monostearate, polyoxyethylene 20 sorbitantristearate

More preferably, the solubilizing agent is a surfactant selected formthe group of co-polymers of ethylene oxide and propylene oxideconforming to the general formula OH(C₂H₄O)_(a)(C₃H₆O)_(b)(C₂H₄O)H. Morepreferably still, the surfactant is selected from the group consistingof LUTROL F68, LUTROL F87, LUTROL 108, LUTROL F127, MYRJ 52, MYRJ 53;most preferably, the surfactant is LUTROL F127.

As used herein, unless otherwise noted, the term “osmopolymer” shallmean a swellable, hydrophilic polymer that interacts with water andswells or expands to a high degree, typically exhibiting a 2-50 foldvolume increase. Suitable examples, include but are not limited topoly(alkylene oxide) of 1 million to 15 million number-average molecularweight, as represented by poly(ethylene oxide), poly(alkalicarboxymethylcellulose) of 500,000 to 3,500,000 number-average molecularweight, wherein the alkali is sodium, potassium or lithium; polymersthat form hydrogels, such as CARBOPOL® acidic carboxypolymer, a polymerof acrylic cross-linked with a polyallyl sucrose, also known ascarboxypolymethylene, and carboxyvinyl polymer having a molecular weightof 250,000 to 4,000,000; CYANAMER® polyacrylamides; cross-linked waterswellable indenemaleic anhydride polymers; GOOD-RITE® polyacrylic acidhaving a molecular weight of 80,000 to 200,000; AQUA-KEEPS® acrylatepolymer polysaccharides composed of condensed glucose units, such asdiester cross-linked polygluran; and the like.

As used herein, unless otherwise noted, the terms “osmoagent”, “osmoticagent” and “osmotically active agent” shall mean an agent which exhibitsan osmotic activity gradient across a semi-permeable membrane. Suitableosmoagents include, but are not limited to, sodium chloride, potassiumchloride, lithium chloride, magnesium sulfate, magnesium chloride,potassium sulfate, sodium sulfate, lithium sulfate, potassium acidphosphate, mannitol, urea, inositol, magnesium succinate, tartaric acid,raffinose, sucrose, glucose, lactose, sorbitol, inorganic salts, organicsalts, carbohydrates, and the like.

Preferred surfactant and structural polymer chemical andcommercial/tradenames may be used interchangeably throughout thespecification herein. For clarity the following is a listing of saidsurfactant and structural polymer chemical and correspondingcommercial/tradenames. Chemical Name Tradename(s) Poloxamer 188PLURONIC ® F68 = LUTROL ® F68 Poloxamer 237 PLURONIC ® F87 = LUTROL ®F87 Poloxamer 338 PLURONIC ® F108 = LUTROL ® F108 Poloxamer 407PLURONIC ® F127 = LUTROL ® F127 Polyoxyl 40 stearate MYRJ ® 52 Polyoxyl50 stearate MYRJ ® 53 Polyethylene oxide of POLYOX ® N10 100,000molecular weight Polyethylene oxide of POLYOX ® N80 200,000 molecularweight Polyethylene oxide of POLYOX ® N 750 300,000 molecular weightPolyethylene oxide of POLYOX ® N 12K 1,000,000 molecular weightPolyethylene oxide of POLYOX ® N 60K 2,000,000 molecular weightPolyethylene oxide of POLYOX ® 303 7,000,000 molecular weight

As used herein, unless otherwise noted, the term “hydrophilic polymer”shall mean any polymer which has an affinity for water. The hydrophilicpolymer may be water-soluble or water-insoluble.

Suitable examples of water soluble hydrophilic polymers include, but arenot limited to, polyvinyl pyrrolidone, polyethylene oxide, polyethyleneglycol, polyvinyl alcohol, polyvinyl alcohol-polyethylene glycolcopolymer, vinyl acetate-vinyl pyrrolidone copolymer, hydroxypropylcellulose, hydroxypropyl methylcellulose, methylcellulose, hydroxyethylcellulose, sodium carboxymethylcellulose, calciumcarboxymethylcellulose, polyvinyl acetate polyethylene glycolco-polymer, starches, maltodextrins, sugars, sorbitol, mannitol,sucrose, gelatin, casein, natural gums, alginates, and the like.Preferably, the water soluble hydrophilic polymer is methylcellulose.

Suitable examples of water insoluble hydropillic polymers include, butare not limited to, polyether, a polyester, cellulose acetate, celluloseacetate butyrate, and a polyacrylate. Another embodiment is a drugformulation, in which the granule coated is additionally comprised of acompound selected from the group consisting of polyethylene glycol,polyoxyethylene-polyoxypropylene copolymer, hydroxypropyl cellulose,glycerin, a citric acid ester, dibutyl sebacate, and the like.

Preferred hydrophilic polymer include, polyethers, such asmethylcellulose or ethyl cellulose; polyesters, such as polyvinylacetate; polyacrylates, such as ethylacrylate-methylmethacrylatecopolymer; citric acid esters, such as triethyl citrate or acetyltriethylcitrate; polyethylene oxide and polyvinyl pyrrolidone (PVP).

Wherein the present invention, the granule coating is comprised of amultiplicity of layers (i.e. two or more layers), the composition ofeach layer is independently selected and may be the same or different.

Preferably, the granule coating is a single layer. More preferably, thegranule coating is a single layer of methylcellulose.

Drug Formulations

The OROS® Push -Pull™ system provides high concentrations of surfactantto enhance dissolution of low solubility drug within the system andprovide the desirable delivery pattern. When a drug tablet formulatedwith a high loading of a low solubility drug imbibes water, the membraneof this system splits open as the push layer presses against the largemass of the drug layer. Incorporating a surfactant within the drug layerdissolves a sufficient fraction of the drug such that the drug layer canbe smoothly extruded through a relatively small delivery port.

While delivery systems comprising high concentrations of solubilizngagent, preferably surfactant, function very well and can easily befabricated by hand compression, these systems are difficult tomanufacture in high-speed power compression. This is because the druglayer granulations containing the high concentrations of solubilizngagents, preferably, surfactants, are pasty and tend to smear on thetablet press. During high-speed tableting, the smeared material canflake off and result in a loss of control over tablet layer weight andof tablet layer composition. FIG. 1 illustrates the smearing problem ofa typical formulation comprising a drug and a solubilizing agent,preferably surfactant, during power compression. The phenomenon observedduring the compression is essentially described as smearing ofgranulated material on the turret of the tablet press. Frictional forcesoccurring during compression produces continuous build up of smearedmaterial on the turret resulting in stopping of the operation in lessthan 15 minutes of run time.

Smearing affects the relative weight of the tablet core composition, andan accompanying loss of ability to control the composition and structureof the compression product.

This invention addresses the issues related to compression of drugcompositions comprising pharmaceutical agent, preferably topiramate anda solubilibizing agent, preferably surfactant. The specificity ofdrug/surfactant combination used in the drug granulation requiresgranule protection in order to eliminate smearing during compression.The approach described in this invention is based on encapsulation ofgranules by a polymer film. The present invention provides a means toproduce drug/surfactant compositions that can be formulated into tabletsunder power compression without smearing.

The surface of a tablet press during power compression of atopiramate/LUTROL F127 composition was clean with no smearing. Thisformulation was in the form of coated granules. The coated granulescompressed well at high speed with minimal or no smearing.

The film properties that are a key to this invention are plasticity andstrength. The present invention provides a means to producedrug/solubilizing agent, preferably, drug/surfactant, compositions thatcan be formulated into tablets under power compression without smearing.

One aspect of the present invention is a drug formulation comprising atablet core made by mechanical compression and comprising a solubilizingagent, preferably surfactant, and a low solubility therapeutic drug,preferably topiramate, in which the solubilizng agent (preferablysurfactant) or drug or both are in coated granules.

Dosage forms in accord with the present invention are manufactured bystandard techniques. For example, the dosage form may be manufactured bya wet granulation technique. In the wet granulation technique, the drugand solubilizing agent, preferably, surfactant, are blended using anorganic solvent, such as denatured anhydrous ethanol, as the granulationfluid. The remaining ingredients can be dissolved in a portion of thegranulation fluid, such as the solvent described above, and this latterprepared solution is slowly added to the drug blend with continualmixing in the blender. The granulating fluid is added until a wet blendis produced, which wet mass blend is then forced through a predeterminedscreen onto oven trays. The blend is dried for 18 to 24 hours at 24° C.to 35° C. in a forced-air oven. The dried granules are then sized. Next,magnesium stearate, or another suitable lubricant, is added to the druggranulation, and the granulation is put into milling jars and mixed on ajar mill for up to 10 minutes. The composition is pressed into a layer,for example, in a Manesty® press or a Korsch LCT press. For a bilayeredcore, the drug-containing layer is pressed and a similarly prepared wetblend of the push layer composition, if included, is pressed against thedrug-containing layer. The intermediate compression typically takesplace under a force of about 50-100 newtons. Final stage compressiontypically takes place at a force of 3500 newtons or greater, often3500-5000 newtons. The single or bilayer compressed cores are fed to adry coater press, e.g., Kilian® Dry Coater press, and subsequentlycoated with the wall materials as described above. A like procedure isemployed for those cores that are manufactured with a push layer andmore than one drug layer, typically on a Korsch multi-layer press.

The present invention also encompasses a drug formulation comprising acapsule core comprised of a semipermeable membrane filled with a mixturecomprising a solubilizing agent, preferably a surfactant and a lowsolubility therapeutic drug, in which the solubiliaing agent (preferablysurfactant) or drug or both are within coated granules.

The coated granules may contain solubiliaing agent (preferablysurfactant) alone, drug alone, or a mixture of drug and solubilizingagent (preferably surfactant). The coated granules may contain othercomponents. These may include a viscosity agent, a binding agent or anosmotic agent.

The granule coating may be continuous or discontinuous. The coating maybe water-soluble. For example the granule coating may be comprised of acompound selected from the group consisting of polyvinyl pyrrolidone,polyethylene oxide, polyethylene glycol, polyvinyl alcohol, polyvinylalcohol-polyethylene glycol copolymer, vinyl acetate-vinyl pyrrolidonecopolymer, hydroxypropyl cellulose, hydroxypropyl methylcellulose,methylcellulose, hydroxyethyl cellulose, sodium carboxymethylcellulose,calcium carboxymethylcellulose, polyvinyl acetate polyethylene glycolco-polymer, a starch, maltodextrin, a sugar, sorbitol, mannitol,sucrose, gelatin, casein, a natural gum, an alginate, and mixturesthereof. Alternatively, the granule coating may be water insoluble. Forexample, the granule coating may be comprised of a compound selectedfrom the group consisting of a polyether (e.g., ethyl cellulose), apolyester (e.g., polyvinyl acetate), cellulose acetate, celluloseacetate butyrate, a polyacrylate (e.g., ethylacrylate-methylmethacrylatecopolymer), and mixtures thereof. Additionally the granule coating maybe comprised of a polyethylene glycol, polyoxyethylene-polyoxypropylenecopolymer, hydroxypropyl cellulose, glycerin, a citric acid ester (e.g.,triethyl citrate or acetyl triethylcitrate or dibutyl sebacate) ormixtures thereof.

The granule coating may be a single layer or a multiplicity of layers.

If a single-layer, the coating is preferably comprised of polyvinylpyrrolidone or polyethylene oxide. The single-layer coating may bebetween about 1% and about 3% of the granule weight or about 24% of thegranule weight, according to the specific properties chosen for thedosage form.

If the coating is a multiplicity of layers, preferably the coatingconsists of two layers. For example, the coating may preferably becomprised of an outer coating layer of methylcellulose and an innercoating layer of polyethylene oxide or polyvinyl pyrrolidone.

As will be described in the following paragraphs, the drug formulationmay be included as a component in a dosage form, preferably a topiramatedosage form, in which the coated granules contain therapeutic drug,preferably, topiramate.

When drug is present in high dosage amounts, greater than 20% of thedrug layer by weight, the present invention may provide a beneficialincreased solubility of the lowly soluble drug to provide for creationof a deliverable drug layer. Additionally, the present invention mayprovide a potentially beneficial increased bioavailability of the lowlysoluble drug by increasing its solubility and wetted surface for greaterbioadhesion to the gastrointestinal tract mucosa. The wetting propertiesof solubilizing agents, preferably surfactants, can also have the effectof preventing the released drug and hydrogel carrier from agglomerating,thereby leading to a more complete spreading of the dispensed drugcomposition onto the absorbable surfaces of the gastrointestinal tractwhich increased surface area provides more absorption surface area toincrease the rate and extent of drug absorbed and increase thetherapeutic response. Moreover, the solubilizing agent, preferablysurfactant may impart adhesive character to the dispensed drug/hydrogelwhich adhesive character can prolong in time the contact that thedrug/hydrogel makes with the absorbable mucosal tissue of thegastrointestinal tract giving more time for the drug to be spread ontoand absorbed once delivered. In yet another potential beneficial effect,the solubilizing agent, preferably surfactant, may additionally increasethe permeability of mucosal membranes to the drug molecule whichpermeability enhancement can lead also to enhanced bioavailability ofthe drug and enhanced therapeutic response.

When drug of the present invention is present in low dosage amounts,less than 20% of drug layer, the present invention may provide abeneficial increased bioavailability of the lowly soluble drug byincreasing its solubility and wetted surface for greater bioadhesion tothe gastrointestinal tract mucosa and enhanced permeability of themucosal surfaces. The increased drug solubility, the increased surfacecontact area on the mucosal tissue, the increased contact time to themucosal tissue, and permeability enhancement of the mucosal tissue tothe drug molecule may individually or compositely contribute to theoverall therapeutic enhancement of the drug by the present invention.

Drug is exemplified herein through the use of topiramate, which is lowlysoluble and therapeutically required to be delivered in high doses.Topiramate is in the therapeutic category of anti-convulsants althoughthe drug may be therapeutic for other indications as well.

Solubility of neat topiramate was measured in de-ionized water at 37degrees centigrade to be 13 mg/ml.

Topiramate Dosage Form

Another present invention is a dosage form for oral administration oftopiramate, comprising a tablet core made by mechanical compression, inwhich the core comprises a solubilizing agent, preferably a surfactant,and topiramate, and in which the solubilizing agent (preferablysurfactant) or topiramate or both are in coated granules.

An aspect of the invention is a topiramate dosage form, furthercomprising an osmotic delivery system (e.g. a push layer) and a tabletcore, in which the osmotic delivery system and the tablet core aresurrounded by a semipermeable membrane having a delivery port throughthe membrane.

Alternatively the tablet core may be incorporated into a matrix deliverysystem. The matrix system may be either an erodible matrix deliverysystem or a non-erodible matrix delivery system.

If the present invention is used in an erodible matrix application, theerodible matrix form further comprises a structural polymer, wherein themolecular weight of the structural polymer is selected to modify theerosion rate of the system. High molecular weight polymers are used toproduce slow erosion rate and slow delivery of drug, low molecularweight polymers produce faster erosion rate and faster release of drug.A blend of high and low molecular weight structural polymers produces anintermediate delivery rate.

If the present invention is used in a nonerodible porous matrix, thenon-eroodible matrix form further comprises a structural polymer whereinthe molecular weight of the structural polymer is selected to provide ahydrogel with viscosity within the pores of the matrix. This viscositysuspends drug particles to promote partial or complete dissolution ofthe drug in the presence of the solubilizing agent, preferablysurfactant, prior to delivery from the pores of the dosage

The present invention is further directed to a topiramate dosage form,which is a controlled release topiramate dosage form.

In an embodiment, the controlled release topiramate dosage formcomprises a push layer (one type of osmotic delivery system), and asemipermeable wall that is positioned over at least a portion of thepush layer.

Sustained release or controlled release dosage forms may be prepared asosmotic dosage forms. Osmotic dosage forms utilize osmotic pressure togenerate a driving force for imbibing fluid into a compartment formed,at least in part, by a semi-permeable wall that permits free diffusionof water but not drug or other components. A significant advantage toosmotic systems is that operation is pH-independent and thus continuesat the osmotically determined rate throughout an extended time period,even as the dosage form transits the gastrointestinal tract andencounters differing microenvironments having significantly different pHvalues. A review of such dosage forms is found in Santus and Baker,“Osmotic drug delivery: a review of the patent literature,” Journal ofControlled Release 35 (1995) 1-21, incorporated in its entirety byreference herein. In particular, the following U.S. Patents, owned bythe assignee of the present application, ALZA Corporation, directed toosmotic dosage forms: U.S. Pat. Nos. 3,845,770; 3,916,899; 3,995,631;4,008,719; 4,111,202; 4,160,020; 4,327,725; 4,519,801; 4,578,075;4,681,583; 5,019,397; and 5,156,850. Such osmotic dosage forms generallycomprise a drug layer, an optional push layer, a semi-permeable membranewhich encompasses the drug and push layers and one or more exitorifices.

In the aqueous environment of the gastrointestinal (GI) tract, water isimbibed through the semi-permeable membrane of the osmotic dosage form,at a controlled rate. This causes the push layer to swell and the drugcomposition(s) to hydrate and form viscous, but deformable, masses. Thepush layer expands against the drug composition(s), which are pushed outthrough the orifice. The drug composition(s) exit the system through theexit orifice in the membrane over prolonged periods of time as waterfrom the gastrointestinal tract is imbibed into the delivery system. Atthe completion of drug release, the biologically inert components of thedosage form are eliminated as a tablet shell.

FIG. 2 is a perspective view of one embodiment of a sustained releaseosmotic dosage form in a standard biconvex round shaped tablet. Dosageform 10 comprises a semi-permeable wall 20 that surrounds and enclosesan internal compartment (not seen in FIG. 2). The internal compartmentcomprises a drug composition comprising a pharmaceutical agent and asolubilizing agent. Semi-permeable wall 20 is provided with at least oneexit orifice 60 for connecting the internal compartment with theexterior environment of use. Accordingly, following oral ingestion ofdosage form 10, water is imbibed through semi-permeable wall 20 and thepharmaceutical agent/drug composition is released through exit 60.

While the geometrical embodiment in FIG. 2 illustrates a standardbiconvex round shaped tablet, the dosage forms of the present inventionmay embrace other geometries including, a capsule shaped caplet, oval,triangular and other shapes designed for oral administration, includingbuccal or sublingual dosage forms.

FIG. 3 is a cutaway view of FIG. 2 showing internal compartment 15containing a single drug composition 30, wherein the drug compositioncomprises pharmaceutical agent 31 in an admixture with selectedexcipients. The excipients may be selected to increase the solubility ofthe drug composition 30 and/or to provide an osmotic activity gradientfor driving fluid from an external environment through semi-permeablewall 20 for forming a deliverable drug composition upon imbibition offluid and/or for other performance and/or manufacturing purposes.

In an embodiment, the present invention is directed to a drugcomposition 30, wherein the drug composition comprises at least onepharmaceutical agent 31, preferably one to two pharmaceutical agents,more preferably one pharmaceutical agent and a solubilizing agent 33.Preferably the pharmaceutical agent 31 is topiramate. Preferably, thesolubilizing agent 33 is a surfactant.

Preferably, drug composition 30 comprises a pharmaceutical agent 31 anda solubilizing agent 33, wherein the pharmaceutical agent 31 is a lowsolubility and/or a low dissolution rate pharmaceutical agent.Preferably, the drug composition of the present invention comprisies atleast about 5%, more preferably, at least about 11%, more preferably, atleast about 17.5%, more preferably, at least about 25%, more preferably,at least about 30%, more preferably, at least about 40%, morepreferably, at least about 42%, more preferably, at least about 45%,solubilizing agent 33, by weight of the drug composition.

In another embodiment of the present invention, as shown in FIG. 3, thedrug composition comprises a pharmaceutical agent 31, a solubilizingagent 33 (represented by vertical dashes) and a structural polymer 32(represented by horizontal dashed lines).

Drug composition 30 excipients may further optionally include alubricant 34 (represented by horizontal wavy lines), an osmoticallyactive agent, also known as an osmoagent 35 (represented by “X” symbols)and/or a suitable binder 36 (represented by large circles).

In operation, following oral ingestion of dosage form 10, the osmoticactivity gradient across the smei-permeable wall 20 causes water of thegastrointestinal tract to be imbibed through the semi-permeable wall 20,thereby forming a deliverable drug composition, e.g., a solution orsuspension or hydrogel, within the internal compartment. The deliverabledrug composition is then released through the exit orifice 60 as watercontinues to enter the internal compartment. As release of the drugcomposition occurs, water continues to be imbibed thereby drivingcontinued release. In this manner, drug is released in a sustained andcontinuous manner over an extended time period.

FIG. 4 is a cutaway view of FIG. 2 with an alternate embodiment ofinternal compartment 15, wherein the internal compartment comprises abi-layer configuration. In this embodiment, internal compartment 15contains a bi-layered compressed core having a first drug composition 30and a push layer 40. Drug composition 30, as described above withreference to FIG. 2 and 3, comprises a pharmaceutical agent and asolubilizing agent, in an admixture with further, optional excipients.

As is described in more detail below, the second component, push layer40, comprises osmotically active component(s), but does not contain anypharmaceutical agent. In an embodiment of the present invention, pushlayer 40 comprises osmopolymer 41. Preferably, the components in pushlayer 40 comprise an osmoagent 42 (represented by very large circles)and one or more osmopolymers 41 (represented by “V” symbols).

Additional, optional excipients within push layer 40, may include binder43 (represented by down-ward triangles), lubricant 44 (represented byupward semi-circles), antioxidant 45 (represented by diagonal lines)and/or colorant 46 (represented by vertical wavy lines).

As water is imbibed through the semi-permeable wall 20, theosmopolymer(s) within push layer 40 swell and push against drugcomposition 30 to thereby facilitate release of the drug compositionthrough the exit orifice 60 and thus the pharmaceutical agent from thedosage form.

In an embodiment of the present invention, drug composition 30, asdescribed with reference to FIGS. 3 and 4 comprises a pharmaceuticalagent (for example, topiramate) and solubilizing agent 33 in anadmixture with further, optional, selected excipients. The excipientsmay be one or more selected from a structural polymer 32, lubricant 34,an osmoagent 35 and/or a binder 36.

In another embodiment of the present invention, push layer 40, asdescribed with reference to FIG. 4, comprises osmotically activecomponents, more specifically an osmoagent 42 and an osmopolymer 41, butdoes not contain any pharmaceutical agent.

FIG. 5 is a view of another embodiment of the present invention, abiconvex round standard tablet as in FIG. 2, wherein the tablet includesa further, optional immediate release coating 50 of a pharmaceuticalagent, preferably topiramate, covering the dosage form of FIG. 2, 3 or4.

More specifically, dosage form 10 of FIG. 5 comprises an overcoat 50 onthe outer surface of semi-permeable wall 20 of dosage form 10. Overcoat50 is a drug composition comprising about 10 μg to about 500 mg of drug31, preferably, overcoat 50 comprises about 10 μg to about 200 mg ofdrug 31, more preferably, overcoat 50 comprises about 5 mg to about 100mg of drug 31 and from about 5 mg to about 200 mg of a pharmaceuticallyacceptable carrier selected from the group consisting of alkylcellulose,hydroxyalkylcellulose and hydroxypropylalkylcellulose. The overcoatpharmaceutically acceptable carrier is represented by a polymer orcopolymer such as methylcellulose, hydroxyethylcellulose,hydroxybutylcellulose, hydroxypropylcellulose,hydroxypropylmethylcellulose, hydroxypropylethylcellulose andhydroxypropylbutylcellulose, polyvinyl pyrrolidone/vinyl acetatecopolymer, polyvinyl alcohol-polyethylene graft copolymer, and the like.Overcoat 50 provides immediate release of the pharmaceutical agent, asovercoat 50 dissolves in the presence of gastrointestinal fluid andconcurrently therewith delivers drug 31 into the gastrointestinal tractfor immediate therapy. Drug 31 in overcoat 50 can be the same ordifferent than the drug 31 in drug composition 30. Preferably drug 31 inovercoat 50 is the same as drug 31 in drug composition 30. Morepreferably drug 31 is topiramate.

FIG. 6 illustrates another, preferred embodiment of the presentinvention, illustrating an open view of a tri-layer capsule shapedosmotic dosage form. FIG. 6 illustrates a capsule shaped tabletembodiment of the present invention comprising a first drug composition30, a second drug composition 70 and a push layer 40. The capsule shapedcore (comprising the first and second drug compositions and the pushlayer) is enveloped by semi-permeable membrane 20. The dosage formfurther comprises at least one exit orifice 60 which exposes the firstdrug composition 30 to the environment of use. The dosage form in FIG. 6further comprises an additional, optional inner membrane 80 that mayfunction as a flow-promoting layer and/or as a smoothing layer and/orcontribute to the control of the rate of imbibition of water into thedosage form.

In an embodiment of the present invention, as described in FIG. 6, theamount and/or concentration of the drug in the first drug composition 30is different than the amount and/or concentration of drug in second drugcomposition 70. In another embodiment of the present invention, theamount and/or concentration of drug in the first drug composition 30 isless than the amount and/or concentration of drug in second drugcomposition 70. Preferably, the amount and/or concentration of drug inthe first drug composition 30 is less than the amount and/orconcentration of drug in the second drug composition 70. Morepreferably, the amounts and/or concentrations of drug in the first andsecond drug compositions are selected to yield a substantially ascendingrate of release of the pharmaceutical agent.

The dosage form illustrated in FIG. 6 may further comprise additionaldrug compositions having varying drug amounts and/or concentrations, toprovide alternate release rates and/or patterns and/or to achievealternate drug plasma concentration profiles that may be preferred.

The drug composition of the present invention comprises two components:(a) a pharmaceutical agent 31, preferably a low solubility and/or lowdissolution rate pharmaceutical agent, more preferably topiramate, and(b) a solubilizing agent 33, preferably a surfactant. In an embodimentof the present invention, the drug composition comprises (a) apharmaceutical agent 31, preferably a low solubility and/or lowdissolution rate pharmaceutical agent, more preferably, topiramate, (b)a solubilizing agent 33, preferably a surfactant and (c) a structuralpolymer 32. The drug composition may further, optionally contain one ormore excipients, as herein described.

In a preferred embodiment of the present invention, the pharmaceuticalagent in drug layer 30 is present in a therapeutically effective amount.In another embodiment of the present invention, the total amount ofpharmaceutical agent present in the drug compostion or compositions ofthe dosage forms of the present invention, is equal to or greater thanthe therapeutically effective, recommended or desired daily dosage.

In an embodiment of the present invention, the pharmaceutical agent indrug composition 30 (or wherein the dosage form comprises more than onedrug composition, the pharmaceutical agent in the combined drugcompositions) is present in an amount equal to or greater than therecommended or desired daily dosage of the pharmaceutical agent to beadministered to a patient in need thereof, thereby permitting once-a-dayor less frequent dosing.

Wherein the dosage form contains more than one drug composition, as forexample in FIG. 6 wherein two drug compositions 30 and 70 are present,each drug composition comprises independently selected (a)pharmaceutical agent 31, preferably a low solubility and/or lowdissolution rate pharmaceutical agent, more preferably topiramate and(b) solubilizing agent 33, preferably surfactant. Each drug compositionmay further optionally contain independently selected structural polymer32 and/or one or more independently selected excipients as hereinafterdescribed.

Wherein two or more drug compositions are present within the dosageforms of the present invention, the daily dosage of the pharmaceuticalagent is present in divided amounts. For example, if the dosage of thepharmaceutical agent is 400 mg, and the dosage form comprises two drugcompositions (e.g. drug compositions 30 and 70 as exemplified in FIG.6), then the sum of the amount of pharmaceutical agent in the first drugcomposition plus the amount of pharmaceutical agent in the second drugcomposition will total 400 mg or more.

Wherein two drug compositions are present with the dosage forms of thepresent invention, the ratio of the drug concentration in the seconddrug composition 70 to the drug concentration in the first drugcomposition 30, as illustrated in FIG. 6, is preferably in the range offrom about 1.0 to about 2.5, preferably, about 1.0 to about 2.0, morepreferably, about 1.25 and about 1.75.

Pharmaceutical agent 31 is preferably a low solubility and/or lowdissolution rate pharmaceutical agent, more preferably, topiramate.Topiramate is in the therapeutic category of anticonvulsants. Thesolubility of neat topiramate is in the range of about 9.8 mg/ml to 13.0mg/ml, with solubility in de-ionized water measured to be about 12mg/ml.

Pharmaceutical agent 31 may be provided in the drug composition in anamount in the range of from about 1 mg to about 750 mg per dosage form.Preferably, the pharmaceutical agent is present in an amount in therange of from about 1 mg to about 250 mg per dosage form, and morepreferably, in the range of from about 5 mg to about 250 mg. The amountof pharmaceutical agent within the dosage form will depend upon therequired dosing level that must be maintained over the delivery period,i.e., the time between consecutive administrations of the dosage forms.In an embodiment of the present invention, the pharmaceutical agent ispresent in an amount in the range of from about 5 mg to about 250 mg,more preferably, in an amount in the range of from about 10 mg to about250 mg per day.

Preferably, pharmaceutical agent 31 is present in the drug compositionin micronized form. Preferably, the micronized pharmaceutical agent hasa nominal particle size of less than about 200 microns, more preferablyless than about 100 microns, most preferably, less than about 50microns.

Solubilizing agent 33, preferably a pharmaceutically acceptablesolubilizing agent, more preferably, a surfactant, is included in thedrug composition(s) of the dosage forms of the present invention, asrepresented by vertical dashes in FIG. 3 and FIG. 4.

It is well known that solubilizing agents, more particularlysurfactants, can be used in liquid drug delivery systems as wettingagents, drug solubilizers, meltable carriers, oily liquid fills in gelcapsules for oral administration, parenteral liquids for injection,ophthalmic drops, topical ointments, salves, lotions, and creams,suppositiories, and in pulmonary and nasal sprays. By their amphipathicmolecular structure comprising opposing polar hydrophilic and non-polarhydrophobic moieties with opposite physical and chemical properties,surfactants are well known to have poor cohesive properties.Accordingly, surfactants have been limited to the above applicationsbecause at room temperature, such surfactants are in the physical formof liquids, pastes, or brittle solids, which physical forms andproperties are generally unacceptable for use as components incompressed solid tablets sufficiently durable for manufacture andpractical use.

As noted, surfactants typically have poor cohesive properties andtherefore do not compress as hard, durable tablets. Furthermore,surfactants are in the physical form of liquid, pastes, or waxy solidsat standard temperatures and conditions and are inappropriate fortabletted oral pharmaceutical dosage forms. However, it has beenunexpectedly found that surfactants may be used in accordance with thedrug compositions and dosage forms of the present invention to enhancethe solubility of the pharmaceutical agent and potentially, thebioavailability of the pharmaceutical agent.

A class of solubilizing agents which may be used in the drugcompositions and/or dosage forms of the present invention include, forexample, a surfactant of POLYOXYL 40 stearate (also known as MYRJ 52)and POLYOXYL 50 stearate (also known as MYRJ 53). Preferably, thesolubilizing agent is a drug solubilizing surfactant selected from thegroup polyethylene glycol (PEG) 3350; PEG 8K; KOLLIDON K90; LUROL F 68,F87, F127, F108; MYRJ 52S; and PVP K2939. Preferably, the solubilizingagent is the surfactant LUTROL F127.

Another class of surfactant which may be used in the drug compositionsand/or dosage forms of the present invention is a group of co-polymersof ethylene oxide and propylene oxide conforming to the general formulaOH(C₂H₄O)_(a)(C₃H₆O)_(b)(C₂H₄O), also known as poloxamers or by theirtradenames PLURONICs and LUTROLs. In this class of surfactants, thehydrophilic ethylene oxide ends of the surfactant molecule and thehydrophobic midblock of propylene oxide of the surfactant molecule serveto dissolve and suspend the drug in the pumpable hydrogel.

Other surfactants that are solids at room temperature and which may beused in the drug compositions and/or dosage forms of the presentinvention include members selected from the group essentially consistingof sorbitan monopalmitate, sorbitan monostearate, glycerol monostearate,polyoxyethlene stearate (self emulsifying), polyoxyethylene 40 sorbitollanolin derivative, polyoxyethylene 75 sorbitol lanolin derivative,polyoxyethylene 6 sorbitol beeswax derivative, polyoxyethylene 20sorbitol beeswax derivative, polyoxyethylene 20 sorbitol lanolinderivative, polyoxyethylene 50 sorbitol lanolin derivative,polyoxyethylene 23 lauryl ether, polyoxyethylene 23 lauryl ether withbutylated hydroxyanisole and citric acid added as preservatives,polyoxyethylene 2 cetyl ether with butylated hydroxyanisole and citricacid added as preservatives, polyoxyethylene 10 cetyl ether withbutylated hydroxyanisole and citric acid added as preservatives,polyoxyethylene 20 cetyl ether with butylated hydroxyanisole and citricacid added as preservatives, polyoxyethylene 2 stearyl ether withbutylated hydroxyanisole and citric acid added as preservatives,polyoxyethylene 10 stearyl ether with butylated hydroxyanisole andcitric acid added as preservatives, polyoxyethylene 20 stearyl etherwith butylated hydroxyanisole and citric acid added as preservatives,polyoxyethylene 21 stearyl ether with butylated hydroxyanisole andcitric acid added as preservatives, polyoxyethylene 20 oleyl ether withbutylated hydroxyanisole and citric acid added as preservatives,polyoxyethylene 40 stearate, polyoxyethylene 50 stearate,polyoxyethylene 100 stearate, sorbitan monopalmitate, sorbitanmonostearate, sorbitan tristearate, polyoxyethylene 4 sorbitanmonostearate, polyoxyethylene 20 sorbitan tristearate, and the like.“Handbook of Pharmaceutical Excipients”, 2^(nd) Ed. Ainley Wade and PaulJ. Weller Editors, 1994.

An especially preferred family of surfactants are a:b:a triblockco-polymers of ethylene oxide:propylene oxide:ethylene oxide. The “a”and “b” represent the average number of monomer units for each block ofthe polymer chain. These surfactants are commercially available fromBASF Corporation of Mount Olive, N.J., in a variety of differentmolecular weights and with different values of “a” and “b” blocks. Forexample, LUTROL® F127 has a molecular weight range of 9,840 to 14,600and where “a” is approximately 101 and “b” is approximately 56, LUTROLF87 represents a molecular weight of 6,840 to 8,830 where “a” is 64 and“b” is 37, LUTROL F108 represents an average molecular weight of 12,700to 17,400 where “a” is 141 and “b” is 44, and LUTROL F68 represents anaverage molecular weight of 7,680 to 9,510 where “a” has a value ofabout 80 and “b” has a value of about 27. A resource of surfactantsincluding solid surfactants and their properties is available inMcCutcheon's Detergents and Emulsifiers, International Edition 1979 andMcCutcheon's Detergents and Emulsifiers, North American Edition 1979.Other sources of information on properties of solid surfactants includeBASF Technical Bulletin PLURONIC & TETRONIC Surfactants 1999 and GeneralCharacteristics of Surfactants from ICI Americas Bulletin 0-1 10/80 5M.

One of the characteristics of surfactants tabulated in these referencesis the HLB value, or hydrophilic lipophilic balance value. This valuerepresents the relative hydroplicility and relative hydrophobicity of asurfactant molecule. Generally, the higher the HLB value, the greaterthe hydrophilicity of the surfactant while the lower the HLB value, thegreater the hydrophobicity. For the LUTROL molecules, for example, theethylene oxide fraction represents the hydrophilic moiety and thepropylene oxide fraction represents the hydrophobic fraction. The HLBvalues of LUTROL F127, F87, F108, and F68 are respectively 22.0, 24.0,27.0, and 29.0.

Other particularly preferred surfactants include sugar estersurfactants, which are sugar esters of fatty acids. Such sugar estersurfactants include sugar fatty acid monoesters, sugar fatty aciddiesters, triesters, tetraesters, or mixtures thereof, although mono-and di-esters are most preferred. Preferably, the sugar fatty acidmonoester comprises a fatty acid having from 6 to 24 carbon atoms, whichmay be linear or branched, or saturated or unsaturated C₆ to C₂₄ fattyacids. The C₆ to C₂₄ fatty acids include C₆, C₇, C₈, C₉, C₁₀, C₁₁, C₁₂,C₁₃, C₁₄, C₁₅, C₁₆, C₁₇, C₁₈, C₁₉, C₂₀, C₂₁, C₂₂, C₂₃, and C₂₄ in anysubrange or combination. These esters are preferably chosen fromstearates, behenates, cocoates, arachidonates, palmitates, myristates,laurates, carprates, oleates, laurates and their mixtures.

Preferably, the sugar fatty acid monoester comprises at least onesaccharide unit, such as sucrose, maltose, glucose, fructose, mannose,galactose, arabinose, xylose, lactose, sorbitol, trehalose ormethylglucose. Disaccharide esters such as sucrose esters are mostpreferable, and include sucrose cocoate, sucrose monooctanoate, sucrosemonodecanoate, sucrose mono- or dilaurate, sucrose monomyristate,sucrose mono- or dipalmitate, sucrose mono- and distearate, sucrosemono-, di- or trioleate, sucrose mono- or dilinoleate, sucrosepolyesters, such as sucrose pentaoleate, hexaoleate, heptaoleate oroctooleate, and mixed esters, such as sucrose palmitate/stearate.

Particularly preferred examples of such sugar ester surfactants includethose sold by the company Croda Inc of Parsippany, N.J. under the namesCRODESTA F10, F50, F160, and F110 denoting various mono-, di- andmono/di ester mixtures comprising sucrose stearates, manufactured usinga method that controls the degree of esterification, such as describedin U.S. Pat. No. 3,480,616. These preferred sugar ester surfactantsprovide the added benefit of tabletting ease and nonsmearinggranulation. The sugar ester surfactants may also provide enhancedcompatibility with sugar based therapeutic agents, exemplified bytopiramate.

Sugar surfactants sold by the company Mitsubishi under the name RYOTOSUGAR ESTERS, for example under the reference B370 corresponding tosucrose behenate formed of 20% monoester and 80% di-, tri- and polyestermay also be used. Use may also be made of the sucrose mono- anddipalmitate/stearate sold by the company Goldschmidt under the name“TEGOSOFT PSE”. Use may also be made of a mixture of these variousproducts. The sugar ester can also be present in admixture with anothercompound not derived from sugar; and a preferred example includes themixture of sorbitan stearate and of sucrose cocoate sold under the name“ARLATONE 2121” by the company ICI. Other sugar esters include, forexample, glucose trioleate, galactose di-, tri-, tetra- or pentaoleate,arabinose di-, tri- or tetralinoleate or xylose di-, tri- ortetralinoleate, or mixtures thereof. Other sugar esters of fatty acidsinclude esters of methylglucose include the distearate of methylglucoseand of polyglycerol-3 sold by the company Goldschmidt under the name ofTEGOCARE 450. Glucose or maltose monoesters can also be included, suchas methyl O-hexadecanoyl-6-D-glucoside and O-hexadecanoyl-6-D-maltose.Certain other sugar ester surfactants include oxyethylenated esters offatty acid and of sugar include oxyethylenated derivatives such asPEG-20 methylglucose sesquistearate, sold under the name “GLUCAMATESSE20”, by the company Amerchol.

Solubilizing agent 33 can be one surfactant or a blend of surfactants.The surfactants are selected such that they have values that promote thedissolution and solubility of the drug. A high HLB surfactant can beblended with a surfactant of low HLB to achieve a net HLB value that isbetween them, if a particular drug requires the intermediate HLB value.Surfactant 33 is selected depending upon the drug being delivered; suchthat the appropriate HLB grade is utilized.

Preferably, the solubilizing agent is selected from the group consistingof MYRJ 52, MYRJ 53, MYRJ 59FL, KOLLIDON 12PF, KOLLIDON 17PF, KOLLIDON25/30, KOLLIDON K90, LUTROL F68, LUTROL F87, LUTROL F127, LUTROL F108;PVP K2932, polyethylene glycol (PEG) 3350; PEG 8K; sorbitanmonopalmitate, sorbitan monostearate, glycerol monostearate,polyoxyethlene stearate, sucrose cocoate, polyoxyethylene 40 sorbitollanolin derivative, polyoxyethylene 75 sorbitol lanolin derivative,polyoxyethylene 6 sorbitol beeswax derivative, polyoxyethylene 20sorbitol beeswax derivative, polyoxyethylene 20 sorbitol lanolinderivative, polyoxyethylene 50 sorbitol lanolin derivative,polyoxyethylene 23 lauryl ether, polyoxyethylene 23 lauryl ether withbutylated hydroxyanisole and citric acid added as preservatives,polyoxyethylene 2 cetyl ether with butylated hydroxyanisole and citricacid added as preservatives, polyoxyethylene 2 stearyl ether,polyoxyethylene 21 stearyl ether, polyoxyethylene 100 stearyl ether,polyoxyethylene 10 cetyl ether with butylated hydroxyanisole and citricacid added as preservatives, polyoxyethylene 20 cetyl ether withbutylated hydroxyanisole and citric acid added as preservatives,polyoxyethylene 2 stearyl ether with butylated hydroxyanisole and citricacid added as preservatives, polyoxyethylene 10 stearyl ether withbutylated hydroxyanisole and citric acid added as preservatives,polyoxyethylene 20 stearyl ether with butylated hydroxyanisole andcitric acid added as preservatives, polyoxyethylene 21 stearyl etherwith butylated hydroxyanisole and citric acid added as preservatives,polyoxyethylene 20 oleyl ether with butylated hydroxyanisole and citricacid added as preservatives, polyoxyethylene 40 stearate,polyoxyethylene 50 stearate, polyoxyethylene 100 stearate, sorbitanmonopalmitate, sorbitan monostearate, sorbitan tristearate,polyoxyethylene 4 sorbitan monostearate, polyoxyethylene 20 sorbitantristearate, and mixtures thereof.

More preferably, the solubilzing agent is a surfactant selected from thegroup consisting of LUTROL F68, LUTROL F87, LUTROL 108, LUTROL F127,MYRJ 52, MYRJ 53; most preferably, the solubilizing agent is thesurfactant LUTROL F127.

In a preferred embodiment of the present invention, the surfactant isnot a sugar ester.

Preferably, in the drug compositions and/or dosage forms of the presentinvention, the pharmaceutical agent is matched with a suitable,aforementioned solubilizing agent, preferably, a solid surfactant ormixture of surfactants.

A suitable surfactant may be selected by preparing aqueous solutions ofselected surfactants spanning a range of HLB values and a range ofconcentrations. Then, the pharmaceutical agent is added in excess to thesurfactant solutions and the saturated solubility of the pharmaceuticalagent (at equilibrium) is measured by an appropriate analytical methodsuch as ultraviolet spectroscopy, chromatographic methods, orgravimetric analysis. The solubility values are then plotted as afunction of HLB and as a function of surfactant concentration. Thesolubilizing agent (preferably surfactant) can then be selected byevaluating the maximum point of solubility generated in the plots at thedifferent concentrations.

Preferably, wherein the pharmaceutical agent is topiramate, thesolubilizing agent is a surfactant, preferably, the surfactant isPLURONIC F127 or its corresponding pharmaceutically acceptable gradeLUTROL F127.

Preferably, the solubilizing agent, preferably surfactant, is present inthe drug composition in micronized form. Preferably, the micronizedsolubilizing agent, preferably surfactant, has a nominal particle sizeof less than about 200 microns, more preferably, less than about 100microns, most preferably, less than about 50 microns.

To achieve a substantially zero order release rate profile, the ratio ofsolubilizing agent, preferably surfactant, to pharmaceutical agent ispreferably, in the range of from about 1.3 to about 2.7, morepreferably, in the range of from about 1.5 to about 2.5, more preferablystill, in the range of from about 1.8 to about 2.2.

To achieve a substantially ascending release rate profile, the ratio ofsolubilizing agent, preferably surfactant, to pharmaceutical agent ispreferably, in the range of from about 0.1:1 to about 3:1, morepreferably, in the range of from about 0.25:1 to about 2.5:1, morepreferably, in the range of from about 0.5:1 to about 2:1, morepreferably still, in the range of from about 1:1 to about 2:1, morepreferably still, in the range of from about 1.5:1 to about 2:1.

The present invention may provide a potentially beneficial increasedbioavailability to the low solubility and/or low dissolution rate drugby increasing its solubility and wetted surface for greater bioadhesionto the gastrointestinal tract mucosa. The wetting properties of thesolubilizing agent (preferably surfactant) may also have the effect ofpreventing the released drug from agglomerating upon release into theenvironment of use, thereby leading to a more complete spreading of thedispensed drug composition onto the absorbable surfaces of thegastrointestinal tract. The resulting increased surface area may providemore absorption surface area to increase the rate and extent of drugabsorbed and thus increase the therapeutic response.

The solubilizing agent (preferably surfactant) may further impartadhesive character to the dispensed drug composition, which adhesivecharacter may prolong the contact time between the drug composition andthe absorbable mucosal tissue of the gastrointestinal tract, therebyproviding more time for the drug to be spread and be absorbed oncedelivered.

In yet another potential beneficial effect, the solubilizing agent(preferably surfactant) may additionally increase the permeability ofmucosal membranes to the drug molecule which permeability enhancementmay lead to enhanced bioavailability of the drug and enhancedtherapeutic response.

When drug 31 is present in low dosage amounts, less than about 20% byweight of the drug composition 30, the present invention may provide abeneficial increased bioavailability of the low solubility and/or lowdissolution rate drug, by increasing its solubility and wetted surfacefor greater bioadhesion to the gastrointestinal tract mucosa andenhanced permeability of the mucosal surfaces. The increased drugsolubility, the increased surface contact area on the mucosal tissue,the increased contact time to the mucosal tissue, and permeabilityenhancement of the mucosal tissue to the drug molecule may individuallyor compositely contribute to the overall therapeutic enhancement of thedrug by the present invention.

Structural polymer 32 comprises any component, for example a hydrophilicpolymer, which provides cohesiveness to the blend so durable tablets canbe made. The structural polymer may also form a hydrogel for viscositycontrol during the operation of the delivery system. The structuralpolymer further suspends the drug particles to promote partial orcomplete solubilization of the drug within the dosage form prior todelivery from the dosage form.

The molecular weight of the structural polymer 32 may be chosen toimpart desired properties to the dosage form, and more particularly tothe drug compositions within the dosage form. High molecular weightpolymers are used to produce a slow hydration rate and slow delivery ofdrug, whereas low molecular weight polymers produce a faster hydrationrate and faster release of drug. A blend of high and low molecularweight structural polymers produces an intermediate delivery rate.

If the drug composition of the present invention is used in an erodiblematrix dosage form, the molecular weight of the structural polymer isselected to modify the erosion rate of the system. High molecular weightpolymers are used to produce slow erosion rate and slow delivery ofdrug, whereas low molecular weight polymers produce a faster erosionrate and faster release of drug. A blend of high and low molecularweight structural polymers produces an intermediate delivery rate.

If the drug composition of the present invention is used in anon-erodible porous matrix dosage form, the molecular weight of thestructural polymer is selected to provide a viscous hydrogel within thepores of the matrix. The viscosity of the hydrogel serves to suspendsdrug particles to promote partial or complete solubilization of the drugin the presence of the surfactant prior to delivery from the pores ofthe dosage form.

Structural polymer 32 is a hydrophilic polymer particle in the drugcomposition that contributes to the controlled delivery of active agent.Representative examples of suitable structural polymers include, but arenot limited to, poly(alkylene oxide) of 100,000 to 750,000number-average molecular weight, including poly(ethylene oxide),poly(methylene oxide), poly(butylene oxide) and poly(hexylene oxide);and a poly(carboxymethylcellulose) of 40,000 to 1,000,000 400,000number-average molecular weight, represented by poly(alkalicarboxymethylcellulose), poly(sodium carboxymethylcellulose),poly(potassium carboxymethylcellulose) poly(calciumcarboxymethylcellulose), and poly(lithium carboxymethylcellulose). Thedrug composition may alternatively comprise ahydroxypropylalkylcellulose of 9,200 to 125,000 number-average molecularweight for enhancing the delivery properties of the dosage form such ashydroxypropylethylcellulose, hydroxypropylmethylcellulose,hydroxypropylbutylcellulose, hydroxypropylpentylcellulose, and the like;and/or a poly(vinylpyrrolidone) of 7,000 to 75,000 number-averagemolecular weight for enhancing the flow properties of the dosage form.Preferred structural polymers are the poly(ethylene oxide) polymers of100,000-300,000 number average molecular weight. Structural polymersthat erode in the gastric environment, i.e., bioerodible structuralpolymers, are especially preferred.

Other structural polymers that may be incorporated into drug composition30 include carbohydrates that exhibit sufficient osmotic activity to beused alone or with other osmoagents. Such carbohydrates comprisemonosaccharides, disaccharides and polysaccharides. Representativeexamples include, but are not limited to, maltodextrins (i.e., glucosepolymers produced by the hydrolysis of grain starch such as rice or cornstarch) and the sugars comprising lactose, glucose, raffinose, sucrose,mannitol, sorbitol, zylitol and the like. Preferred maltodextrins arethose having a dextrose equivalence (DE) of about 20 or less, preferablymaltodextrins with a DE ranging from about 4 to about 20, and morepreferably from about 9 to about 20. Maltodextrins having a DE of about9-12 and molecular weight of about 1,600 to 2,500 are preferred.

The carbohydrates described above, preferably the maltodextrins, may beused in the drug composition 30 without the addition of an osmoagent, toyield the desired release of pharmaceutical agent from the dosage form,while providing a therapeutic effect over a prolonged period of time andup to 24 hours with once-a-day dosing.

Preferably, the structural polymer is selected form the group consistingof poly(ethylene oxide), poly(methylene oxide), poly(butylene oxide) andpoly(hexylene oxide); poly(carboxymethylcellulose), poly(alkalicarboxymethylcellulose), poly(sodium carboxymethylcellulose),poly(potassium carboxymethylcellulose) poly(calciumcarboxymethylcellulose), poly(lithium carboxymethylcellulose),hydroxypropylcellulose, hydroxypropylethylcellulose,hydroxypropylmethylcellulose, hydroxypropylbutylcellulose,hydroxypropylpentylcellulose, poly(vinylpyrrolidone), bioerodiblestructural polymers (carriers), maltodextrins, polyvinyl pyrrolidones,polyvinylpyrrolidone vinyl acetate copolymers, lactose, glucose,raffinose, sucrose, mannitol, sorbitol, zylitol and mixtures thereof.

More preferably, the structural polymer is selected from the groupconsisting of MALTRIN M100, POLYOX N10 and POLYOX N80, most preferably,the structural polymer is POLYOX N80.

It has been further found that, when present, the structural polymer andsolubilizing agent (preferably surfactant) are preferably present in thedrug composition in a certain amounts. Preferably, the structuralpolymer should be present in an amount less than or equal to about 90%by weight of the drug composition and the surfactant should be presentin amount between 0 and about 50% by weight of the drug composition.Preferably, for high dosages, the structural polymer should be presentin an amount less than or equal to about 30% by weight of the drugcomposition, more preferably in an amount less than about 20% by weightof the drug composition; and the surfactant should be present in amountgreater than or equal to about 15% by weight of the drug composition,more preferably, in an amount greater than or equal to about 25% byweight of the drug composition, more preferably still, in an amountgreater than or equal to about 35% by weight of the drug composition,most preferably, in an amount greater than or equal to about 40% byweight of the drug composition.

For high dosages, a preferred range of concentration of structuralpolymer within the drug composition of osmotic delivery systems is fromabout 5% to about 50% weight percent of polyoxyethylene 200,000molecular weight (POLYOX N80), with an especially preferred range offrom 0 to about 20% by weight of the drug composition.

For low dosages, a preferred range of concentration of structuralpolymer within the drug composition of osmotic delivery systems is fromabout 50% to about 90% weight percent of polyoxyethylene 200,000molecular weight (POLYOX N80), with an especially preferred range offrom 75% to about 90% by weight of the drug composition.

Lubricant 34 may optionally be included in the drug composition asrepresented by a horizontal wavy line in FIG. 3 and FIG. 4. Lubricant 34is used during tablet manufacture to prevent adherence to die walls orpunch faces. Typical lubricants include, but are not limited to,magnesium stearate, sodium stearate, stearic acid, calcium stearate,magnesium oleate, oleic acid, potassium oleate, caprylic acid, sodiumstearyl fumarate, and magnesium palmitate or blends of such lubricants.The amount of lubricant present in the drug composition is preferably,in the range of from about 0.01 to about 20 mg.

Binder 36, preferably a therapeutically acceptable vinyl polymer binder,may also be optionally included in the drug composition as representedby small circles in FIG. 3 and FIG. 4. Representative binders include,but are not limited to vinyl polymer binder, acacia, starch and gelatin.Wherein the binder is a vinyl polymer, the vinyl polymer comprises a5,000 to 350,000 average molecular weight, represented by a memberselected from the group consisting of poly-n-vinylamide,poly-n-vinylacetamide, poly(vinyl pyrrolidone), also known aspoly-n-vinylpyrrolidone, poly-n-vinylcaprolactone,poly-n-vinyl-5-methyl-2-pyrrolidone, and poly-n-vinylpyrrolidonecopolymers with a member selected from the group consisting of vinylacetate, vinyl alcohol, vinyl chloride, vinyl fluoride, vinyl butyrate,vinyl laureate, and vinyl stearate. Representative other binderssuitable for formulation in the drug composition include, but are notlimited to acacia, starch and gelatin. The binder present within thedrug composition is preferably, in an amount in the range of from about0.01 to about 25 mg.

Disintegrants may also be optionally included in the drug composition.Disintegrants may be selected from starches, clays, celluloses, alginsand gums and crosslinked starches, celluloses and polymers.Representative disintegrants include, but are not limited to, cornstarch, potato starch, croscarmelose, crospovidone, sodium starchglycolate, VEEGUM HV, methylcellulose, agar, bentonite,carboxymethylcellulose, alginic acid, guar gum, low-substitutedhydroxypropyl cellulose, microcrystalline cellulose, and the like.

In an embodiment of the present invention, at least one drug compositionwithin a dosage form comprises a pharmaceutical agent and a solubilizingagent. Preferably, the pharmaceutical agent is topiramate and thesolubilizing agent is a surfactant, more preferably, the solubilizingagent is the surfactant PLURONIC F127 or its correspondingpharmaceutically acceptable grade LUTROL F127.

It has further been found that the surfactant appears to be capable ofoperating as both a structural polymer as well as a surfactant, and assuch it may be utilized as the sole excipient in the drug composition.

Wherein a drug composition comprises pharmaceutical agent 31,solubilizing agent 33, preferably a surfactant, and structural polymer32, the amount of structural polymer 32 and surfactant 33 formulatedwithin said drug composition must be appropriately selected andcontrolled.

One skilled in the art will recognize that the amounts of solubilizingagent and structural polymer are selected to optimize thecharacteristics of the drug layer composition. The amounts are selectedsuch that the dosage form maintains structural integrity beforeadministration and upon administration, the drug layer compositionhydrates and is capable of being pushed out of the dosage form providinga desired release pattern.

In an embodiment of the present invention is a drug composition, whereinthe pharmaceutical agent is topitamate and wherein the topiramate ispresent in amount in the range of about 10 mg to about 200 mg. Infurther embodiments of the present invention are drug compositionswherein topiramate is present in 10 mg, 20 mg, 40 mg, 45 mg, 80 mg, 90mg, 120 mg, 135 mg, 160 mg, 180 mg and 200 mg amount.

In an embodiment of the present invention is a dosage form comprisingone or more drug compositions, preferably one to two drug compositions,wherein the total amount of topiramate present within the dosage form(i.e. the total amount present within the drug compositions) is in anamount in the range of about 10 mg to about 200 mg. In furtherembodiments of the present invention are dosage forms comprising one ortwo drug compositions wherein the total amount of topiramate present is10 mg, 20 mg, 40 mg, 45 mg, 80 mg, 90 mg, 120 mg, 135 mg, 160 mg, 180 mgor 200 mg amount.

In an embodiment of the present invention is a dosage form comprising afirst drug composition comprising pharmaceutical agent, preferably a lowsolubility and/or low dissolution rate solubilizing agent, morepreferably topiramate and a solubilizing agent, preferably surfactant;and a second drug composition comprising pharmaceutical agent,preferably a low solubility and/or low dissolution rate solubilizingagent, more preferably topiramate and a solubilizing agent, preferablysurfactant.

In another embodiment of the present invention is a dosage formcomprising (a) a core comprising a first drug composition comprisingpharmaceutical agent, preferably a low solubility and/or low dissolutionrate solubilizing agent, more preferably topiramate and a solubilizingagent, preferably surfactant; and a push layer comprising anosmopolymer; (b) a semi-permeable wall surrounding said core and (c) anexit orifice through the semi-permeable wall for releasing thepharmaceutical agent from the dosage form over a prolonged period oftime.

In yet another embodiment of the present invention is a dosage formcomprising (a) a core comprising a first drug composition comprisingpharmaceutical agent, preferably a low solubility and/or low dissolutionrate solubilizing agent, more preferably topiramate and a solubilizingagent, preferably surfactant; a second drug composition comprisingpharmaceutical agent, preferably a low solubility and/or low dissolutionrate solubilizing agent, more preferably topiramate and a solubilizingagent, preferably surfactant; and a push layer comprising anosmopolymer; (b) a semi-permeable wall surrounding said core and (c) anexit orifice through the semi-permeable wall for releasing thepharmaceutical agent from the dosage form over a prolonged period oftime.

One skilled in the art will recognize will that wherein the dosage formsof the present invention comprise a first drug composition comprising apharmaceutical agent and a solubilizing agent; and a second drugcomposition comprising a pharmaceutical agent and a solubilizing agent;then the pharmaceutcal agent in the first and second drug compositionsmay be the same or different and the solubilizing agent on the first andsecond drug compostions my be the same or different. One skilled in theart will further recognize that additional, optional components withinthe first and second drug compositions, for example structural polymer,binder, lubricant, and the like, when present in both the first andsecond drug compositions may similarly be the same or different.

The formulations and processes for the manufacture of the push layer 40,the semi-permeable wall 20 and the exit orifice(s) 60 are well known inthe art. The components and processes for the manufacture of the pushlayer, semi-permeable wall and exit orifice(s) are also brieflydescribed below.

Push layer 40 comprises a displacement composition in contacting,layered arrangement with drug composition 30 as illustrated in FIG. 4.Wherein more than one drug composition is present in the dosage form (asin FIG. 6), the push layer 40 is preferably in contacting, layeredarrangement with only one of the drug compositions.

In an embodiment of the present invention push layer 40 comprises anosmopolymer. In another embodiment of the present invention, push layer40 comprises an osmopolymer and an osmoagent.

Push layer 40 comprises osmopolymer 41 that imbibes water and swells topush the drug composition of the drug layer(s) through the exit orificeof the dosage form. The osmopolymers are swellable, hydrophilic polymersthat interact with water and swell or expand to a high degree, typicallyexhibiting a 2-50 fold volume increase. The osmopolymer can benon-crosslinked or crosslinked. Preferably, push layer 40 comprises fromabout 20 to about 375 mg of osmopolymer 41, represented by “V” symbolsin FIG. 4.

Wherein osmopolymers are present in both a drug composition and the pushlayer, the osmopolymer 41 in the push layer 40 possesses a highermolecular weight than the osmopolymer in drug composition. For example,such a situation may be found wherein the structural polymer in the drugcomposition is an osmopolymer.

Representatives of osmopolymers (i.e. fluid-imbibing displacementpolymers) comprise members selected from poly(alkylene oxide) of 1million to 15 million number-average molecular weight, as represented bypoly(ethylene oxide), and poly(alkali carboxymethylcellulose) of 500,000to 3,500,000 number-average molecular weight, wherein the alkali issodium, potassium or lithium. Examples of alternate osmopolymerscomprise polymers that form hydrogels, such as CARBOPOL® acidiccarboxypolymer, a polymer of acrylic cross-linked with a polyallylsucrose, also known as carboxypolymethylene, and carboxyvinyl polymerhaving a molecular weight of 250,000 to 4,000,000; CYANAMER®polyacrylamides; cross-linked water swellable indenemaleic anhydridepolymers; GOOD-RITE® polyacrylic acid having a molecular weight of80,000 to 200,000; AQUA-KEEPS® acrylate polymer polysaccharides composedof condensed glucose units, such as diester cross-linked polygluran; andthe like. Representative polymers that form hydrogels are known to theprior art in U.S. Pat. No. 3,865,108, issued to Hartop; U.S. Pat. No.4,002,173, issued to Manning; U.S. Pat. No. 4,207,893, issued toMichaels; and in Handbook of Common Polymers, Scott and Roff, ChemicalRubber Co., Cleveland, Ohio.

Push layer 40 further, optionally, comprises an osmotically effectivecompound, osmoagent 42, represented by large circles in FIG. 4.Preferably, the osmoagent 42 comprises up to about 40% by weight of thepush layer, more preferably, from about 5% to about 30% by weight of thepush layer, more preferably still, from about 10% to about 30% by weightof of the push layer. Osmotically effective compounds are known also asosmoagents and/or as osmotically effective solutes. Preferably, pushlayer 40 comprises an osmoagent.

Osmoagents 42, which may be found in the drug composition and/or thepush layer in the dosage forms of the present invention are those thatexhibit an osmotic activity gradient across the wall 20. Suitableosmoagents include, but are not limited to, sodium chloride, potassiumchloride, lithium chloride, magnesium sulfate, magnesium chloride,potassium sulfate, sodium sulfate, lithium sulfate, potassium acidphosphate, mannitol, urea, inositol, magnesium succinate, tartaric acid,raffinose, sucrose, glucose, lactose, sorbitol, inorganic salts, organicsalts, carbohydrates, and the like.

Push layer 40 may further optionally comprises a pharmaceuticallyacceptable binder 43, such as a vinyl polymer, represented by trianglesin FIG. 4. The vinyl polymer comprises a 5,000 to 350,000viscosity-average molecular weight, represented by a member selectedfrom the group consisting of poly-n-vinylamide, poly-n-vinylacetamide,poly(vinyl pyrrolidone), also known as poly-n-vinylpyrrolidone,poly-n-vinylcaprolactone, poly-n-vinyl-5-methyl-2-pyrrolidone, andpoly-n-vinylpyrrolidone copolymers with a member selected from the groupconsisting of vinyl acetate, vinyl alcohol, vinyl chloride, vinylfluoride, vinyl butyrate, vinyl laureate, and vinyl stearate. Push layer40 preferably contains from about 0.01 to about 25 mg of vinyl polymer.

Push layer 40 may further optionally comprise from 0 to about 5 mg of anontoxic colorant or dye 46, identified by vertical wavy lines in FIG.2. Suitable examples of colorant or dye 46 include Food and DrugAdministration Colorants (FD&C), such as FD&C No.1 blue dye, FD&C No. 4red dye, red ferric oxide, yellow ferric oxide, titanium dioxide, carbonblack, indigo, and the like.

Push layer 40 may further optionally comprise lubricant 44, identifiedby half circles in FIG. 4. Suitable examples include, but are notlimited to, a member selected from the group consisting of sodiumstearate, potassium stearate, magnesium stearate, stearic acid, calciumstearate, sodium oleate, calcium palmitate, sodium laurate, sodiumricinoleate and potassium linoleate, and blends of such lubricants. Theamount of lubricant included in the push layer 40 is preferably in therange of from about 0.01 to about 10 mg.

Push layer 40 may further optionally comprise an antioxidant 45,represented by slanted dashes in FIG. 4, wherein the antioxidant ispresent to inhibit the oxidation of ingredients within the push layer.Push layer 40 comprises from 0.0 to about 5 mg of an antioxidant.Representative antioxidants include, but are not limited to, ascorbicacid, ascorbyl palmitate, butylated hydroxyanisole, a mixture of 2 and 3tertiary-butyl-4-hydroxyanisole, butylated hydroxytoluene, sodiumisoascorbate, dihydroguaretic acid, potassium sorbate, sodium bisulfate,sodium metabisulfate, sorbic acid, potassium ascorbate, vitamin E,4-chloro-2,6-ditertiary butylphenol, alpha-tocopherol, andpropylgallate.

Semi-permeable wall 20, sometimes also referred to as a membrane, isformed to be permeable to the passage of external water. Semi-permeablewall 20 is also substantially impermeable to the passage of thecomponents of the drug composition and push layer, such as drug,solubilizing agent, structural polymer, osmagent, osmopolymer and thelike. As such, wall 20 is semi-permeable. The selectively semi-permeablecompositions used for forming the semi-permeable wall 20 are essentiallynon-erodible and are substantially insoluble in biological fluids duringthe life of the dosage form.

Representative polymers suitable for forming semi-permeable wall 20comprise semi-permeable homopolymers, semi-permeable copolymers, and thelike. Such materials include, but are not limited to, cellulose esters,cellulose ethers and cellulose ester-ethers. The cellulosic polymershave a degree of substitution (DS) of their anhydroglucose unit of fromgreater than 0 up to 3, inclusive. Degree of substitution (DS) means theaverage number of hydroxyl groups originally present on theanhydroglucose unit that are replaced by a substituting group orconverted into another group. The anhydroglucose unit can be partiallyor completely substituted with groups such as acyl, alkanoyl, alkenoyl,aroyl, alkyl, alkoxy, halogen, carboalkyl, alkylcarbamate,alkylcarbonate, alkylsulfonate, alkysulfamate, semi-permeable polymerforming groups, and the like, wherein the organic moieties contain fromone to twelve carbon atoms, and preferably from one to eight carbonatoms.

Semi-permeable wall 20 may further compromise a semi-permeable polymerselected from the group consisting of cellulose acylate, cellulosediacylate, cellulose triacylate, cellulose acetate, cellulose diacetate,cellulose triacetate, mono-, di- and tri-cellulose alkanylates, mono-,di-, and tri-alkenylates, mono-, di-, and tri-aroylates, and the like.Exemplary polymers include cellulose acetate having a DS in the range ofabout 1.8 to about 2.3 and an acetyl content in the range of about 32 toabout 39.9%; cellulose diacetate having a DS in the range of about 1 toabout 2 and an acetyl content in the range of about 21 to about 35%;cellulose triacetate having a DS in the range of about 2 to about 3 andan acetyl content in the range of about 34 to about 44.8%; and the like.Preferred cellulosic polymers include cellulose propionate having a DSof about 1.8 and a propionyl content of about 38.5%; cellulose acetatepropionate having an acetyl content in the range of about 1.5 to about7% and an acetyl content in the range of about 39% to about 42%;cellulose acetate propionate having an acetyl content in the range ofabout 2.5% to about 3%, an average propionyl content in the range ofabout 39.2% to about 45%, and a hydroxyl content in the range of about2.8% to about 5.4%; cellulose acetate butyrate having a DS of about 1.8,an acetyl content in the range of about 13% to about 15%, and a butyrylcontent in the range of about 34% to about 39%; cellulose acetatebutyrate having an acetyl content in the range of about 2% to about 29%,a butyryl content in the range of about 17% to about 53%, and a hydroxylcontent in the range of about 0.5% to about 4.7%; cellulose triacylateshaving a DS in the range of about 2.6 to about 3, such as cellulosetrivalerate, cellulose trilamate, cellulose tripalmitate, cellulosetrioctanoate and cellulose tripropionate; cellulose diesters having a DSin the range of about 2.2 to about 2.6, such as cellulose disuccinate,cellulose dipalmitate, cellulose dioctanoate, cellulose dicaprylate, andthe like; and mixed cellulose esters, such as cellulose acetatevalerate, cellulose acetate succinate, cellulose propionate succinate,cellulose acetate octanoate, cellulose valerate palmitate, celluloseacetate heptanoate, and the like. Semi-permeable polymers are known inU.S. Pat. No.4,077,407, and they can be synthesized by proceduresdescribed in Encyclopedia of Polymer Science and Technology, Vol. 3, pp.325-354 (1964), Interscience Publishers Inc., New York, N.Y.

Additional semi-permeable polymers that may be used for formingsemi-permeable wall 20 comprise cellulose acetaldehyde dimethyl acetate;cellulose acetate ethylcarbamate; cellulose acetate methyl carbamate;cellulose dimethylaminoacetate; semi-permeable polyamide; semi-permeablepolyurethanes; semi-permeable sulfonated polystyrenes; cross-linkedselectively semi-permeable polymers formed by the coprecipitation of ananion and a cation, as disclosed in U.S. Pat. Nos. 3,173,876; 3,276,586;3,541,005; 3,541,006 and 3,546,142; semi-permeable polymers, asdisclosed by Loeb, et al. in U.S. Pat. No. 3,133,132; semi-permeablepolystyrene derivatives; semi-permeable poly(sodium styrenesulfonate);semi-permeable poly(vinylbenzyltrimethylammonium chloride); andsemi-permeable polymers exhibiting a fluid permeability of 10⁻⁵ to 10⁻²(cc. mil/cm hr.atm), expressed as per atmosphere of hydrostatic orosmotic pressure differences across a semi-permeable wall. The polymersare known to the art in U.S. Pat. Nos. 3,845,770; 3,916,899 and4,160,020; and in Handbook of Common Polymers, Scott and Roff (1971) CRCPress, Cleveland, Ohio. Wall 20 can optionally be formed as two or morelamina such as described in U.S. Pat. No. 6,210,712.

Preferably, the semi-permeable wall 20 comprises a polymer selected fromthe group consisting of cellulose acetate and cellulose acetatebutyrate.

Semi-permeable wall 20 may further, optionally, comprise aflux-regulating agent. The flux regulating agent is a compound added toassist in regulating the water permeability or flux throughsemi-permeable wall 20. The flux-regulating agent can be aflux-enhancing agent or a flux-decreasing agent. The flux-regulatingagent can therefore be pre-selected to increase or decrease the flux ofthe external water through the semi-permeable membrane. Flux-regulatingagents that produce a marked increase in permeability to fluid such aswater are often essentially hydrophilic, while those that produce amarked decrease to fluids such as water are essentially hydrophobic. Theamount of flux-regulator in semi-permeable wall 20 when incorporatedtherein is preferably in the range of from about 0.01% to about 25% byweight or more.

Suitable flux-regulating agents include, but are not limited to,polyhydric alcohols, polyalkylene glycols, polyalkylenediols, polyestersof alkylene glycols, and the like.

Flux enhancers include, but are not limited to, polyethylene glycol 300,400, 600, 1500, 4000, 6000 and the like; low molecular weight glycolssuch as polypropylene glycol, polybutylene glycol and polyamyleneglycol: the polyalkylenediols such as poly(1,3-propanediol),poly(1,4-butanediol), poly(1,6-hexanediol), and the like; aliphaticdiols such as 1,3-butylene glycol, 1,4-pentamethylene glycol,1,4-hexamethylene glycol, and the like; alkylene triols such asglycerine, 1,2,3-butanetriol, 1,2,4-hexanetriol, 1,3,6-hexanetriol andthe like; esters such as ethylene glycol dipropionate, ethylene glycolbutyrate, butylene glycol dipropionate, glycerol acetate esters, and thelike. Preferred flux enhancers include the group of difunctionalblock-copolymer of ethylene oxide and propylene oxide conforming to thegeneral formula OH(C₂H₄O)_(a)(C₃H₆O)_(b)(C₂H₄O)H, known as PLURONIC®co-polymers (sold in pharmaceutical grade under the trade name LUTROL).

Flux-decreasing agents include, but are not limited to, phthalatessubstituted with an alkyl or alkoxy or with both an alkyl and alkoxygroup such as diethyl phthalate, dimethoxyethyl phthalate, dimethylphthalate, and [di(2-ethylhexyl) phthalate], aryl phthalates such astriphenyl phthalate, and butyl benzyl phthalate; polyvinyl acetates,triethyl citrate, Eudragit; insoluble salts such as calcium sulfate,barium sulfate, calcium phosphate, and the like; insoluble oxides suchas titanium oxide; polymers in powder, granule and like form such aspolystyrene, polymethylmethacrylate, polycarbonate, and polysulfone;esters such as citric acid esters esterified with long chain alkylgroups; inert and substantially water impermeable fillers; resinscompatible with cellulose based wall forming materials, and the like.

Other materials may be further, optionally, included in thesemi-permeable wall composition for imparting flexibility and/orelongation properties, i.e. to make semi-permeable wall 20 less brittleand/or to render tear strength to semi-permeable wall 20. Suitablematerials include, but are not limited to, phthalate plasticizers suchas dibenzyl phthalate, dihexyl phthalate, butyl octyl phthalate,straight chain phthalates of six to eleven carbons, di-isononylphthalte, di-isodecyl phthalate, and the like. Plasticizers includenonphthalates such as triacetin, dioctyl azelate, epoxidized tallate,tri-isoctyl trimellitate, tri-isononyl trimellitate, sucrose acetateisobutyrate, epoxidized soybean oil, and the like. The amount ofplasticizer in semi-permeable wall 20 when incorporated therein ispreferably in the range of from about 0.01% to about 20% weight, orhigher.

Exit orifice 60 is provided in each osmotic dosage form. Exit 60 mayencompass one or more exit orifices. Exit 60 cooperates with the drugcomposition(s) within the dosage form for the uniform release of drugfrom the dosage form. The exit can be provided during the manufacture ofthe dosage form or during drug delivery by the dosage form in a fluidenvironment of use.

Exit 60 may include an orifice that is formed or formable from asubstance or polymer that erodes, dissolves or is leached from the outerwall to thereby form an exit orifice. The substance or polymer mayinclude, for example, an erodible poly(glycolic) acid or poly(lactic)acid in the semi-permeable wall; a gelatinous filament; awater-removable poly(vinyl alcohol); a leachable compound, such as afluid removable pore-former selected from the group consisting ofinorganic and organic salt, oxide, carbohydrate, and the like.

The exit 60, or a plurality of exits, can alternatively be formed byleaching a member selected from the group consisting of sorbitol,lactose, fructose, glucose, mannose, galactose, talose, sodium chloride,potassium chloride, sodium citrate and mannitol to provide auniform-release dimensioned pore-exit orifice.

Exit 60 can have any shape, such as round, triangular, square, oval,elliptical, and the like, for the uniform metered dose release of a drugfrom the dosage form.

When more than one exit orifice is present in the dosage form, the exitsmay be present in spaced-apart relation on one or more surfaces of thedosage form, provided that at least one of the exit orifices is situatedsuch that they expose drug composition to the external environment.

The drug compositions of the present invention may be prepared accordingto known methods, for example as a granulation, as a dry blend, as aco-precipitate, as a roller compacted blend, and the like. Preferably,the drug composition is prepared as a granulation.

A variety of processing techniques can be used to promote uniformity ofmixing between the pharmaceutical agent 31 and solubilizing agent,preferably surfactant, 33 in drug composition 30. In one method, thedrug and surfactant are each micronized to a nominal particle size ofless than about 200 microns, preferably, to a nominal particle size ofless than about 100 microns, more preferably, to a nominal particle sizeof less than about 50 microns. Standard micronization processes such asjet milling, cryogrinding, bead milling, and the like, may be used.

Alternatively, the drug and solubilizing agent may be dissolved in acommon solvent to produce mixing at the molecular level and co-dried toa uniform mass. The resulting mass may be ground and sieved to afree-flowing powder. The resulting free-flowing powder may be further,optionally, granulated with wet mass sieving or fluid bed granulationwith any optional structural polymer to form a drug composition (in theform of a granulation) of the present invention.

Alternatively still, pharmaceutical agent 31 and solubilizing agent 33may be melted together at elevated temperature to mix the drug insolubilizing agent, preferably surfactant, and then congealed to roomtemperature. The resulting solid may be ground, sized, and optionally,further granulated with structural polymer.

In yet another manufacturing process, pharmaceutical agent 31 andsolubilizing agent 33 may be dissolved in a common solvent or blend ofsolvents and spray dried to form a co-precipitate that is then further,optionally incorporated with structural polymer by standard granulationprocessing by fluid bed processing or wet mass sieving.

In yet another manufacturing process, pharmaceutical agent 31 andsolubilizing agent 33 may be dissolved in a common solvent or blend ofsolvents which pharmaceutical agent/surfactant solution is then sprayedonto the optional structural polymer directly in a fluid bed granulationprocess.

The drug composition of the present invention may then be formulatedinto the dosage forms of the present invention. Drug composition 30within the dosage form is preferably formed by compression of thepharmaceutical agent 31, solubilizing agent 33, preferably surfactant,and if present, the structural polymer 32. For the preparation ofosmotic dosage forms, one or more drug compositions are compressed in astacked orientation, with a push layer prepared and incorporated intothe dosage form in contacting relation to at least one of the drugcompositions.

Each drug composition is prepared by mixing the pharmaceutical agent 31with the solubilizing agent 33 and any additional components (e.g.structural polymer 32) into a uniform mixture.

Alternatively, the drug composition 30 may be formed from particles bycomminution that produces the size of the pharmaceutical agent and thesize of any accompanying polymers used in the fabrication of the drugcomposition, typically as a core containing the compound. Means forproducing such particles include, but are not limited to, granulation,spray drying, sieving, lyophilization, crushing, grinding, jet milling,micronizing and chopping to produce the intended micron particle size.The process can be performed by size reduction equipment, such as amicropulverizer mill, a fluid energy grinding mill, a grinding mill, aroller mill, a hammer mill, an attrition mill, a chaser mill, a ballmill, a vibrating ball mill, an impact pulverizer mill, a centrifugalpulverizer, a coarse crusher, a fine crusher, and the like. The size ofthe particle(s) can be ascertained by screening, including a grizzlyscreen, a flat screen, a vibrating screen, a revolving screen, a shakingscreen, an oscillating screen, a reciprocating screen and the like. Theprocesses and equipment for preparing drug and/or carrier particles aredisclosed in Remington's Pharmaceutical Sciences, 18th Ed., pp.1615-1632(1990); Chemical Engineers Handbook, Perry, 6th Ed., pp. 21-13 to 21-19(1984); Journal of Pharmaceutical Sciences, Parrot, Vol. 61, No. 6, pp.813-829 (1974); and Chemical Engineer, Hixon, pp. 94-103 (1990).

Exemplary solvents suitable for manufacturing drug compositions and/orthe push layer for the dosage form comprise aqueous or inert organicsolvents that do not adversely harm the materials used in the system.Such solvents include, but are not limited to, members selected from thegroup consisting of aqueous solvents, alcohols, ketones, esters, ethers,aliphatic hydrocarbons, halogenated solvents, cycloaliphatics,aromatics, heterocyclic solvents and mixtures thereof. Suitable examplesof solvents include, but are not limited to, acetone, diacetone alcohol,methanol, ethanol, isopropyl alcohol, butyl alcohol, methyl acetate,ethyl acetate, isopropyl acetate, n-butyl acetate, methyl isobutylketone, methyl propyl ketone, n-hexane, n-heptane, ethylene glycolmonoethyl ether, ethylene glycol monoethyl acetate, methylenedichloride, ethylene dichloride, propylene dichloride, carbontetrachloride nitroethane, nitropropane tetrachloroethane, ethyl ether,isopropyl ether, cyclohexane, cyclooctane, benzene, toluene, naphtha,tetrahydrofuran, diglyme, water, aqueous solvents containing inorganicsalts such as sodium chloride, calcium chloride, and the like, andmixtures thereof such as acetone and water, acetone and methanol,acetone and ethyl alcohol, methylene dichloride and methanol, andethylene dichloride and methanol.

Push layer 40 may be similarly prepared according to known methods, forexample according to the processes described above, by mixing theappropriate ingredients under appropriate conditions (e.g. osmoagent,omsopolymer, etc.).

Semi-permeable wall 20 may be similarly perpeared accoding to knownmethods, for example by pan coating, by mixing the appropriateingredients and applying the resulting mixture to dosage form.

Dosage form components (e.g. drug composition(s), push layer,semi-permebale wall, exit orifice, etc.) may be combined to form thedosage forms of the present invention according to standard techniquesknown in the art. More specifically, the dosage form core, comprisingone or more drug compositions, and when present the push layer, isprepared first, preferably by compression. The semi-permeable wall isthen coated onto the core and one or more exit orifices are providedthrough the semi-permeable wall to expose one or more drug compositionsto the external environment.

For example, the dosage form may be manufactured by the wet granulationtechnique. In the wet granulation technique, the drug, optionalstructural polymer and solubilizing agent, preferably surfactant, areblended using an organic solvent, such as denatured anhydrous ethanol,as the granulation fluid. Any additional excipients can then bedissolved in a portion of the granulation fluid, such as the solventdescribed above, and this latter prepared solution is slowly added tothe drug blend with continual mixing in the blender. The granulatingfluid is added until a wet blend is produced, which wet mass blend isthen forced through a predetermined screen onto oven trays. The blend isdried for 18 to 24 hours at 24° C. to 35° C. in a forced-air oven. Thedried granules are then sized. Next, magnesium stearate, or anothersuitable lubricant, is added to the drug granulation, and thegranulation is put into milling jars and mixed on a jar mill for up to10 minutes. The composition is pressed into a layer, for example, in aManesty® press or a Korsch LCT press.

For a bi-layered core (i.e. a dosage form which comprises a drugcomposition and a push layer), the drug composition is pressed and asimilarly prepared granulation of the push layer is pressed against thedrug composition. This intermediate compression typically takes placeunder a force of about 50-100 newtons. Final stage compression typicallytakes place at a force of 3500 newtons or greater, often 3500-5000newtons.

Wherein the core comprises two or more drug compositions and a pushlayer, each drug composition, prepared as described above isindividually compressed. The push layer is then pressed against at leastone of the drug compositions, in an intermediate compression step asdescribed above. Final compression of the multi-layer core is thenapplied as described above.

Single, bi-layer or multi-layer compressed cores are then fed to a drycoater press, e.g., Kilian® Dry Coater press, and subsequently coatedwith the semi-permeable wall materials, according to known methods.

In another process of manufacture the drug and other ingredientscomprising the drug composition are blended and pressed into a solidlayer. The layer possesses dimensions that correspond to the internaldimensions of the area the layer is to occupy in the dosage form, and italso possesses dimensions corresponding to the push layer, if included,for forming a contacting arrangement therewith. The drug and otheringredients can also be blended with a solvent and mixed into a solid orsemisolid form by conventional methods, such as ballmilling,calendering, stirring or rollmilling, and then pressed into a.preselected shape. Next, if included, the push layer components areplaced in contact with the drug composition in a like manner. Thelayering of the drug composition(s) and the push layer can be fabricatedby conventional two-layer press techniques. The compressed cores maythen be coated with the semi-permeable wall material, according to knownmethods.

Another manufacturing process that can be used comprises blending thepowdered ingredients for each layer in a fluid bed granulator. After thepowdered ingredients are dry blended in the granulator, a granulatingfluid, for example, poly(vinylpyrrolidone) in water, is sprayed onto thepowders. The coated powders are then dried in the granulator. Thisprocess granulates all the ingredients present therein while adding thegranulating fluid. After the granules are dried, a lubricant, such asstearic acid or magnesium stearate, is mixed into the granulation usinga blender e.g., V-blender or tote blender. The granules are then pressedin the manner described above.

Pan coating may be conveniently used to provide semi-permeable wall 20of the completed osmotic dosage forms. In the pan coating system, thewall-forming composition (comprising the semi-permeable polymer andoptional, additional materials) is deposited by successive spraying ofthe appropriate wall composition onto the compressed single, bi-layeredor mulit-layered core (which ore comprises the drug layer(s) and, wherepresent, the push layer), accompanied by tumbling in a rotating pan. Apan coater is often used because of its availability at commercialscale.

Other known coating techniques may alternatively be used for coating thecompressed core. For example, semi-permeable wall 20 of the dosage formmay be formed in one technique using the air-suspension procedure. Thisprocedure consists of suspending and tumbling the compressed single,bi-layer or multi-layer core in a current of warmed air and thesemi-permeable wall forming composition, until the semi-permeable wallis applied to the core. The air-suspension procedure is well suited forindependently forming the semi-permeable wall of the dosage form. Theair-suspension procedure is described in U.S. Pat. No. 2,799,241; in J.Am. Pharm. Assoc., Vol. 48, pp. 451-459 (1959); and, ibid., Vol. 49, pp.82-84 (1960). The dosage form may alternatively be coated with aWurster® air-suspension coater using, for example, methylene dichloridemethanol as a cosolvent for the wall forming material. An Aeromatic®air-suspension coater may alternatively be used employing a suitableco-solvent.

Once coated, semi-permeable wall 20 is dried in a forced-air oven or ina temperature and humidity controlled oven to free the dosage form ofany solvent(s) used in the manufacturing. Drying conditions areconventionally chosen on the basis of available equipment, ambientconditions, solvents, coatings, coating thickness, and the like.

Preferably, the drug compositions, the push layer and/or the dosageforms are dried to remove volatile organic and in-organic solvents tolevels that are pharmaceutically acceptable and/or optimal formanufacturing. More preferably, the drug compositions, the push layerand/or the dosage forms are to less than about 10% moisture, morepreferably still, to less than about 5% moisture, most preferably lessthan about 3% moisture.

One or more exit orifices are provided according to known methods, forexample by drilling, in the drug composition end of the dosage form.Alternatively, one or more exit orifices may be provided in the drugcomposition end of the dosage form by erosion or leaching.

The dosage form can therefore be constructed with one or more exits inspaced-apart relation on one or more surfaces of the dosage form.

Drilling, including mechanical and laser drilling, through thesemi-permeable wall can be used to form the exit orifice. Such exits andequipment for forming such exits are disclosed in U.S. Pat. No.3,916,899, by Theeuwes and Higuchi and in U.S. Pat. No.4,088,864, byTheeuwes, et al.

Leachable or eroable exit orfices may be formed or formable from asubstance or polymer that erodes, dissolvces or is leached from theouter semi-permeable (outer) wall to thereby form an exit orifice. Thesubstance or polymer may include for example, an erodiblepoly(glucolic)acid or poly(lactic)acid in the semi-permeable wall, agelatinous filament, a water removable poly(vinyl)alcohol, a leachablecompound such as a fluid removable pore former, for exa,pel an inorganicor organic salt, oxide or carbohydrate. The exit or plurality of exitscan be formed by leaching a member selected from the group consisting ofsorbitol, lactose, fructose, glucose, mannose, galactose, talose, sodiumchloride, potassium chloride, sodium citrate and mannitol to provide auniform release dimensioned pore exit orifice. The exit can have anyshape, such as, round, triangular, square, elliptical, and the like.

The dosage form may be further, optionally coated with additional watersoluble overcoats, which may be colored (e.g., OPADRY colored coatings)or clear (e.g., OPADRY Clear).

The dosage form may further, optionally comprise a smoothing coat, whichsmoothing coat is applied to the compressed drug core, according toknown methods, prior to the application of the semi-permeable wall.Suitable examples of formulations and components which may used in thesmoothing coat include, but are not limited to, hydroxypropylcellulose,hydroxyethylcellulose, methylcellulose, hydroxypropyl methylcellulose,and the like. The coating may further optionally contain polyethyleneglycol of 400 to 6000 molecular weight, polyvinyl pyrrolidone of 2500 to1,000,000 molecular weight, and the like.

The dosage forms of the present invention provide controlled release ofpharmaceutical agent, preferably topiramate, over a prolonged period oftime, preferably, for greater than about 1 hour, more preferably, for atleast about 4 hours, more preferably still, for at least about 8 hours,more preferably, for at least about 10 hours, more preferably still, forat least about 14 hours, more preferably still, for at least 18 hours,more preferably still, for at least 20 hours, more preferably still forat least 22 hours, more preferably still for up to about 24 hours.Preferably, the dosage forms of the present invention provide controlledrelease of pharmaceutical agent for about 2 to about 24 hours, morepreferably, for about 4 to about 24 hours.

In an embodiment of the present invention, the release of drug from thedosage forms of the present invention provides efficacious therapy forabout 24 hours. In another embodiment of the present invention, thedosage form releases drug for about 16 to about 24 hours afteradministration.

In an embodiment of the present invention, the dosage form comprises anoptional immediate release drug overcoat which provides immediate drugdelivery (i.e. within less than about 1 hour after administration) andcontrolled drug delivery continuing thereafter until the dosage formceases to release drug, preferably, at least about 8 hours, morepreferably, about 12 hours, more preferably still, about 16 hours, morepreferably still about 18 hours, more preferably still, about 22 hours,more preferably still, about 24 hours.

Representative dosage forms of the present invention exhibit T₇₀ valuesof greater than about 8 hours, preferably, greater than about 10 hours,more preferably, greater than about 12 hours, more preferably still,greater than about 16 hours, and release drug, preferably topiramate,for a continuous period of time of more than about 12 hours, morepreferably, for more than about 16 hours, more preferably still, forabout 24 hours.

Within about 2 hours following administration, representative dosageforms of the present invention release drug, preferably topiramate, at asubstantially zero order rate of release or at a substantially ascendingrate of release, depending upon the composition of drug composition(s)and push layers. Preferably, drug release continues for a prolongedperiod of time. Following the prolonged period of delivery, drugcontinues to be delivered for several more hours until the dosage formis spent or expelled from the GI tract.

In a bi-layer embodiment of once-a-day dosage forms in accord with thepresent invention, the dosage forms have a T₇₀ of about 15 hours toabout 18 hours, preferably, about 17 hours, and provided release ofdrug, preferably topiramate, for a continuous period of time,preferably, for at least about 24 hours. Preferably, the dosage formreleases drug with a substantially zero order rate of release.

In a tri-layer embodiment of the present invention, the dosage form ofthe present invention comprises two drug compositions and a push layer,wherein the amount and/or concentration of drug in the first drugcomposition is less than the amount and/or concentration of drug in thesecond drug composition. Representative tri-layer dosage forms of thepresent invention exhibit T₇₀ values of greater than about 8 hours,preferably, greater than about 12 hours, more preferably, greater thanabout 14 hours, and release drug, preferably topiramate, for acontinuous period of time of more than about 16 hours, preferably forabout 24 hours. Preferably, the dosage form releases drug with asubstantially ascending rate of release.

In an embodiment of the present invention, the dosage forms of thepresent invention release the pharmaceutical agent (drug) at variousrates of release between about 1%/hr and about 12%/hr over a prolongedperiod of time.

In an embodiment of the present invention, the dosage forms releasepharmaceutical agent with a substantially zero order rate of release. Inanother embodiment of the present invention, the dosage forms releasepharmaceutical agent with a substantially ascending rate of release. Inyet another embodiment of the present invention, the dosage formsrelease pharmaceutical agent with a release rate which results in asubstantially ascending drug plasma concentration.

The present invention is further directed to a method of treatmentcomprising administering any of the drug compositions or dosage forms ofthe present invention, to a patient in need thereof. Said drugcompositions and/or dosage forms comprise pharmaceutical agent,preferably topiramate, in the range of from about 1 mg to about 750 mg.

The method, in one embodiment, comprises administering orally to apatient in need thereof, a pharmaceutical agent, preferably topiramate,administered from a dosage form comprising the desired amount of saidpharmaceutical agent and solubilizing agent, preferably surfactant.

The present invention further provides methods for administeringpharmaceutical agent, preferably topiramate, to a patient, and methodsfor producing a desired drug plasma concentration of topiramate. In anembodiment of the present invention is a method for administering orallyto a patient in need thereof, a dosage form that administers at acontrolled rate, over a continuous period of time up to about 24 hours,drug for its intended therapy. In another embodiment of the presentinvention, the method comprises administering orally to a patient inneed thereof, a therapeutic dose of pharmaceutical agent, preferablytopiramate, from a single dosage form that administers the topiramateover about 24 hours.

The present invention is further directed to a method of treatmentcomprising administering to a patient in need thereof, an oralcontrolled release dosage form of a pharmaceutical agent, preferablytopiramate, wherein the pharmaceutical agent is released from the dosageform in a substantially zero order rate of release.

The present invention is further directed to a method of treatingcomprising administering to a patient in need thereof, an oralcontrolled release dosage form of a pharmaceutical agent, preferablytopiramate, wherein the pharmaceutical agent is released from the dosageform in a substantially ascending rate of release.

The present invention is further directed to a method of treatingcomprising administering to a patient in need thereof, an oralcontrolled release dosage form of a pharmaceutical agent, preferablytopiramate, wherein the pharmaceutical agent is released from the dosageform at a rate which results in a substantially ascending drug plasmaconcentration.

The present invention is further directed to a method of treating adisorder is selected from the group consisting of epilepsy, migraine,glaucoma and other ocular disorders (including diabetic retinopathy),essential tremor, restless limb syndrome, obesity, weight loss, Type IIDiabetes Mellitus, Syndrome X, impaired oral glucose tolerance, diabeticskin lesions, cluster headaches, neuralgia, neuropathic pain (includingdiabetic neuropathy), elevated blood glucose levels, elevated bloodpressure, elevated lipids, bipolar disorder, dementia, depression,psychosis, mania, anxiety, schizophrenia, OCD, PTSD, ADHD, impulsecontrol disorders (including bulimia, binge eating, substance abuse,etc.), ALS, asthma, autism, autoimmune disorders (including psoriasis,rheumatoid arthritis, etc.), chronic neurodegenerative disorders, acuteneurodegeneration, sleep apnea and other sleep disorders or forpromoting wound healing, comprising administering to a patient in needthereof, any of the drug compositions or dosage forms of the presentinvention.

Preferably, the disorder is selected from the group consisting ofepilepsy, migraine, diabetic retinopathy, diabetic neuropathy, diabeticskin lesions, obesity, weight loss, Type II Diabetes Mellitus, SyndromeX, impaired oral glucose tolerance, elevated blood glucose levels andelevated blood pressure.

In an embodiment, the push layer comprises a displacement composition incontacting layered arrangement with the tablet core as shown in FIG. 2.The push layer comprises an osmopolymer that imbibes an aqueous orbiological fluid and swells to push the drug composition through theexit port through the semipermeable membrane. A polymer having suitableimbibition properties may be referred to herein as an osmopolymer. Theosmopolymers are swellable, hydrophilic polymers that interact withwater and aqueous biological fluids and swell or expand to a highdegree, typically exhibiting a 2-50 fold volume increase. Theosmopolymer can be non-crosslinked or crosslinked.

Preferably, the push layer comprises about 20 to about 375 mg ofosmopolymer. Preferably, the osmopolymer in the push layer possesses ahigher molecular weight than the osmopolymer in drug layer.

Representatives of fluid-imbibing displacement polymers comprise membersselected from poly(alkylene oxide) of 1 million to 15 millionnumber-average molecular weight, as represented by poly(ethylene oxide),and poly(alkali carboxymethylcellulose) of 500,000 to 3,500,000number-average molecular weight, wherein the alkali is sodium, potassiumor lithium. Examples of additional polymers for the formulation of thepush-displacement composition comprise osmopolymers comprising polymersthat form hydrogels, such as Carbopol® acidic carboxypolymer, a polymerof acrylic cross-linked with a polyallyl sucrose, also known ascarboxypolymethylene, and carboxyvinyl polymer having a molecular weightof 250,000 to 4,000,000; Cyanamer® polyacrylamides; cross-linked waterswellable indenemaleic anhydride polymers; Good-rite® polyacrylic acidhaving a molecular weight of 80,000 to 200,000; Aqua-Keeps® acrylatepolymer polysaccharides composed of condensed glucose units, such asdiester cross-linked polygluran; and the like. Representative polymersthat form hydrogels are known to the prior art in U.S. Pat. No.3,865,108, issued to Hartop; U.S. Pat. No. 4,002,173, issued to Manning;U.S. Pat. No.4,207,893, issued to Michaels; and in Handbook of CommonPolymers, Scott and Roff, Chemical Rubber Co., Cleveland, Ohio.

In an embodiment, the push layer comprises 0 to about 75 mg, andpreferably, about 5 to about 75 mg of an osmotically effective compound,an osmoagent. The osmotically effective compounds are known also asosmoagents and as osmotically effective solutes. The osmoagent that maybe found in the drug layer and the push layer in the dosage form arethose that exhibit an osmotic activity gradient across the semipermeablemembrane. Suitable osmoagents comprise a member selected from the groupconsisting of sodium chloride, potassium chloride, lithium chloride,magnesium sulfate, magnesium chloride, potassium sulfate, sodiumsulfate, lithium sulfate, potassium acid phosphate, mannitol, urea,inositol, magnesium succinate, tartaric acid, raffinose, sucrose,glucose, lactose, sorbitol, inorganic salts, organic salts andcarbohydrates.

The push layer may further comprises a therapeutically acceptable vinylpolymer. The vinyl polymer comprises a 5,000 to 350,000viscosity-average molecular weight, represented by a member selectedfrom the group consisting of poly-n-vinylamide, poly-n-vinylacetamide,poly(vinyl pyrrolidone), also known as poly-n-vinylpyrrolidone,poly-n-vinylcaprolactone, poly-n-vinyl-5-methyl-2-pyrrolidone, andpoly-n-vinylpyrrolidone copolymers with a member selected from the groupconsisting of vinyl acetate, vinyl alcohol, vinyl chloride, vinylfluoride, vinyl butyrate, vinyl laureate, and vinyl stearate. Push layerpreferably comprises about 0.01 to about 25 mg of vinyl polymer.

The push layer may further comprise 0 to 5 mg of a nontoxic colorant ordye. The colorant includes Food and Drug Administration Colorant (FD&C),such as FD&C No.1 blue dye, FD&C No. 4 red dye, red ferric oxide, yellowferric oxide, titanium dioxide, carbon black, and indigo.

The push layer may further comprise a lubricant. Typical lubricantscomprise a member selected from the group consisting of sodium stearate,potassium stearate, magnesium stearate, stearic acid, calcium stearate,sodium oleate, calcium palmitate, sodium laurate, sodium ricinoleate andpotassium linoleate, and blends of such lubricants. In an embodiment,the amount of lubricant included in the push layer 40 is about 0.01 toabout 10 mg.

The push layer may further comprise an antioxidant to inhibit theoxidation of ingredients comprising expandable formulation. In anembodiment, the push layer comprises 0.00 to about 5 mg of anantioxidant. Representative antioxidants comprise a member selected fromthe group consisting of ascorbic acid, ascorbyl palmitate, butylatedhydroxyanisole, a mixture of 2 and 3 tertiary-butyl-4-hydroxyanisole,butylated hydroxytoluene, sodium isoascorbate, dihydroguaretic acid,potassium sorbate, sodium bisulfate, sodium metabisulfate, sorbic acid,potassium ascorbate, vitamin E, 4-chloro-2,6-ditertiary butylphenol,alpha-tocopherol, and propylgallate.

The controlled release topiramate dosage form may be composed of coatedgranules comprising both topiramate and a solubilizing agent, preferablya surfactant. The coated granules may further comprise a viscosity agentor a binding agent or both.

One advantage of the present invention is the ability to modify thecontent and amount of the granule coating and granule composition tomodify the release rate of topiramate from the dosage form.

For example, the composition of the controlled release topiramate dosageform may be selected by which the release rate of topiramate is at itsmaximum value for at least two hours in an in vitro release rate assay.

Alternatively, the composition of the controlled release topiramatedosage form may be selected by which the release rate of topiramate isat its maximum value for at least three hours, four hours, six hours,eight hours, ten hours or at least 12 hours in an in vitro release rateassay.

Alternatively still, the composition of the controlled releasetopiramate dosage form may be selected by which the maximum release rateof topiramate is reached after about 1 hour, 1.5 hours, 2 hours, 2.5hours, 3 hours, 4 hours, 5 hours, 6.5 hours, 8 hours, 10 hours, 12hours, 14 hours or 16 hours in an in vitro release rate assay.

EXEMPLIFIED DESCRIPTION OF THE INVENTION

The following examples are illustrative of the present invention andthey should not be considered as limiting the scope of the invention inany way, as these examples and other equivalents thereof will becomeapparent to those versed in the art in light of the present disclosure,drawings and accompanying claims.

Example 1

For purposes of comparison a conventional topiramate drug formulationwas prepared as follows.

First, a binder solution was prepared. 3 kg of polyvinylpyrrolidone(K29-32; average molecular weight of 40,000) was dissolved in 17 kg ofwater. Then, the 17.28 kg of Topiramate, 5.75 kg of Polyethylene oxideN-80 (approximately 2 million molecular weight) and 32.16 kg ofPoloxamer 407 and 1.5 kg of polyvinylpyrrolidone identified as K29-32were added to a fluid bed granulator bowl. The dry materials werefluidized and mixed while 10 kg of binder solution was sprayed from 3nozzles onto the powder. The granulation was dried in the fluid-bedchamber to an acceptable moisture level. The coated granules were sizedusing a Fluid Air mill with a 7-mesh screen. The granulation wastransferred to a tote tumbler, mixed with 12 g of butylatedhydroxytoluene and lubricated with 1.2 kg of stearic acid and 600 g ofmagnesium stearate.

FIG. 1 shows the smearing observed with the conventional formulationwithout the use of the coated granules.

Example 2

1 kilogram of coated granules was fabricated as follows.

304 grams of topiramate free acid, 566 grams of LUTROL F127, and 30grams of polyvinyl pyrrolidone 12PF (PVP) were passed through a #40 meshsieve and dry mixed. Prior to this sizing operation, the drug particlesize was nominally about 100 microns and the LUTROL F127 had beenmicronized to a finely divided size. 100 grams of POLYOX N80 was passedthrough a #50 mesh sieve and blended into the mixture. The mixed powderswere introduced to a small bowl mixer. The mixer was started and whilemixing the powders, 100 ml of anhydrous ethanol was slowly andcontinuously added to the mixture, forming a uniform, damp mass. Thedamp mass was removed from the mixer and spread on open trays to airdried overnight in a fume hood. The dried mass was then passed through a#20 mesh sizing sieve.

The resulting bulk granules were transferred to a mini-Glatt fluid bedgranulator (FBG) and fluidized in a current of warm, drying air. Asolution of wall-forming polymer was spray coated onto the granules. Thesolution consisted of 5 weight percent PVP 12PF dissolved in water. Thespraying continued until the granules accumulated a PVP wall coatingweight of 24 percent. During the spraying process, the bed of granuleswas removed four times and passed each time through a #16 mesh sizingscreen to break up agglomerates. The bed of granules was also sizedthrough the 16-mesh sieve after the 24 weight percent had been coated.

The PVP-coated granules were returned to the FBG unit and spray coatedwith a second wall-forming composition. This solution consisted of 5weight percent methylcellulose A15LV (MC) dissolved in water. Thissecond solution was spray coated onto the granules and small samples ofthe granules were removed during the process at weight gainsrepresenting 1%, 2% and 3% MC. Each fraction was sized through a #16screen. This produces coated granules with diameters of about 1.2millimeters (47 mils).

These processes formed four batches of coated granules, one sample ofgranules coated with a single layer of PVP and three batches of granulescoated with bilayers of PVP/MC.

Samples of the bare core granule (prior to any coating), granules with24% PVP, granules with 24% PVP+1% MC, granules with 24% PVP+2% MC, andgranules with 24% PVP+3% MC were assembled for comparative testing fortheir smear resistance. A small portion of each was placed on a hardflat surface at room temperature. Each sample was pressed and shearedmanually with a spatula to test smearing. The resistance to smearing wasobserved as follows: bare granules <<0% MC<1% MC<2% MC<3% MC. Therelatively thick layer of PVP provided a thick subcoat for more completecoverage of the granule core. The thin, cellulosic top coat providedimproved resistance to crushing and smearing.

Example 3

Solubilizing granules of nearly equivalent granule core and coatingcomposition to the granules described in Example 2 were made at the 30kg scale using pilot manufacturing scale equipment. The resulting coatedgranules were fed to a Korsch multiplayer press to assess smearing.After formulating these granules into tablets for about 30 minutes, thesurface of the press turret was clean and almost completely free ofsmeared material.

Delivery systems were then hand fabricated with this batch of coatedgranules and tested for release of drug. The performance of thesesystems with coated granules at the 30 kg scale was compared to theperformance of systems encapsulated at the 1 kg scale by measuringrelease rates.

FIG. 8 shows topiramate release patterns of control release topiramatedosage forms having coated granules prepared in the 1 kg and 30 kg batchsizes. The results show that the release patterns of both productionsystems were equivalent. That is, no differences were found in the timeto reach the maximum release rate, the magnitude of the maximum releaserate, and the period in which the maximum release rate is maintained.

Example 4

The coated granules of Example 3 were compressed manually into tabletswith push layers. The drug layer weights were fixed at 182 mg and thepush layer weight were fixed at 60 mg. Drug contents were about 45 mg.The resulting tablets were coated with rate controlling membranes(semi-permeable membranes), drilled with 40 mil ports, and dried.

FIG. 9 shows how bilayer granule coatings can extend the period of zeroorder release kinetics. In all cases the first layer of the granulecoating was 23% PVP. An outer, second layer containing MC was added. Acomparison of release patterns obtained with 0% MC and 3% MC granulecoating layer show that the bilayer granule coating can extend theperiod of zero order drug delivery. That is, the 3% MC second layerextended the zero order release rate by at least two hours.

Example 5

A polyethylene oxide encapsulated drug formulation of the invention wasprepared as follows.

First, an encapsulation solution was prepared. 4.5 kg of Polyethyleneoxide N-10 (approximately 1 million molecular weight) was dissolved in70.5 kg of water. Then, 26 kg of the drug granulation described inExample 4 was added to a fluid bed granulator bowl. The granulation wasfluidized and mixed while 50 kg of coating solution was sprayed from anozzle onto the powder. The coated granules were dried in the fluid-bedchamber to an acceptable moisture level. The coated granules were sizedusing a Fluid Air mill with a 7-mesh screen. The granulation wastransferred to a Gemco rotational tumbler, mixed with 5.6 g ofbutylhydroxytoluene and lubricated with 565 g of stearic acid.

The use-test was performed using a Korsch multilayer press. Thefeasibility of the method was clearly demonstrated: no smearing of thedrug granulation on the turret was observed over the 30 minute run time.Original (non-encapsulated) granulation used as a control (Example 1)showed considerable smearing in the first 5 minutes of compression atequivalent parameters (See FIG. 1).

Example 6

Coated granules with cores comprising topiramate, LUTROL F127, POLYOXN80, and PVP were encapsulated at the 1 kg scale according to theprocedures described in Example 2 with wall (semi-permeable wall)compositions and weights of 23% PVP inner coating layer and a 3% MCouter coating layer. Four batches of coated granules were encapsulatedwith this bilayer wall. Each batch represented a different ratio ofsolubilizing surfactant to drug. Delivery systems were fabricated byhand following the procedures in Example 2 and tested for release ofdrug.

FIG. 10 represents the release profiles of the resulting systems. Drugrelease was 99% by 24 hours. System-to-system uniformity was excellentfor LUTROL F127/drug ratios ranging from 1.86 to 1.18. Variability wasobserved at a Lutrol F127/Drug ratio=0.93. Therefore, the optimal ratioof topiramate/LUTROL F127 within the granules is in the range of about1.9 to 1.2 inclusive. The lower the ratio, the greater the period ofzero order release, the later the time to reach the maximum release rateand the greater the magnitude of the maximum release rate.

Example 7

Changes in the granule coating can modulate the rate of drug delivery.FIG. 11 shows how changing bilayer coatings of topiramate granules canalter the delivery rate. Two compositions were prepared. Granulescontaining 28.8/53.6/9.58/1/0.02. topiramate/LUTROL F127/PVPK2932/POLYOX N80/stearic acid/Mg stearate/ BHT, were coated with 23% MC.The first was a bilayer consisting of a 23% PVP inner coating layer witha 3% MC outer coating layer. The second were the granules coated with amonolayer of 10% POLYOX N10. The results show a difference in themagnitude of the maximum release rate: the bilayer significantly loweredthe maximum value of the release rate.

Example 8

To test the effect that single-layer coating weight can have on smearresistance, a formulation was prepared from 35/52/10/3topiramate/micronized LUTROL F127/POLYOX N80/PVP 12 PF. This mixture wascoated to the target percentage weight with methylcellulose A15LV toform coated granules. These coated granules, 180 mg, were compressedwith a 60 mg push layer (60 mg of 73.7/20/5/1/0.25, POLYOX303/NaCl/PVPK2932/Fe₂O₃/stearic acid/BHT). Smear resistance was assessed by force toeject tablets from die in manual compression mode.

The results of tests are shown in FIG. 12. Resistance to smearing with3% MC was poor, with 4% MC was fair and with 7% or greater MC,resistance was good. FIG. 12 shows dosage forms comprising 13% MC coatedgranules (a) have a period of zero order release kinetics that isextended by 2 hours compared to 3% MC; (b) have a delay of more than 2hours in the time to reach maximum release rate compared to 3% MC.

Example 9

To test the effect that bilayer coating can have on smear resistance, aformulation was prepared from 35/52/10/3 topiramate/micronized LUTROLF127/POLYOX N80/PVP 12 PF. This mixture was coated to the targetpercentage weight with PVP 12PF followed by methylcellulose A15LV toform coated granules. These coated granules, 180 mg, were compressedwith a 60 mg push layer (60 mg of 73.7/20/5/1/0.25, POLYOX303/NaCl/PVPK2932/Fe₂O₃/stearic acid/BHT). The tablets were covered by a 1 milsmooth coat of 90/10 HEC/LUTROL F127, and two membrane—a membrane of 6mils (1 mil=1/1000^(th) of an inch) thickness composed of of 55/40/5EC100 cps/HPC EFX/MYRJ 52S and a membrane of 6 mils of 70/30 CA 398-10/Polaxamer 188, with a 1×40 mil orifice. Smear resistance was assessedby force to eject tablets from die in manual compression mode. Releaserate was measured using USP II methods.

The results are shown in FIG. 13. The results show that the bilayercoating imparts smear resistance compared to single walls. The releasepatterns also show that smear resistance can be achieved withoutchanging the release properties of the dosage form in an in vitro assay.

Example 10

Granules were prepared as in Example 8 and coated with bilayers. Theinner layer was 10% PVP and various weight percentages of MC wereapplied to the outer coating layer: 3%, 7% and 10%. FIG. 14 shows howchanging single-layer coating weight modulates the time to reach amaximum delivery rate of topiramate. Increasing MC weight percentage inthe outer coating layer increased the time to reach maximum release rateand decreased the period of zero order release rate.

Example 11 Bi-Layered Osmotic Dosage Form of Topiramate

A drug composition of the present invention was prepared as follows.Aqueous solutions of five surfactants were prepared. The selectedsurfactants were four grades of ethylene oxide/propylene oxide/ethyleneoxide (LUTROL grades F127, F87, F 108, and F68) and PEG-40 stearate(MYRJ 52). Solutions were made at concentrations of 1, 5, and 15 weightpercent. The aqueous surfactant blends solutions were chilled asnecessary to promote complete dissolution of the surfactant prior todrug solubility studies. Each surfactant had a different HLB value andspanned a range of 16.9 to 29 HLB units.

The aqueous surfactant solutions were equilibrated to constanttemperature in a 37° C. water bath. Then, neat topiramate drug was addedslowly with stirring in about 10 mg increments to the surfactantsolutions until no more drug dissolved. A control sample of drugdissolved in de-ionized water without surfactant was included forcomparison purposes. The resulting saturated solutions of drug werefiltered through 0.8 micron filters and analyzed for drug concentrationby refractive index chromatography. The resulting solubility values wereplotted as a function of both surfactant concentration and thehydrophilic-lipophilic balance value of each surfactant.

This method revealed three insights. Topiramate solubility in water wasincreased by each surfactant. Drug solubility was higher in the presenceof each surfactant compared to the control where the solubility inde-ionized water without surfactant was 13.0 mg/ml. Second, a highconcentration of surfactant was more effective in solubilizing drug thana low concentration. Third, the HLB values most effective to increasesolubility of this drug were at the lower end, in the range of 16.9 to22. The three concentrations of surfactant each formed the maximumsolubility of topiramate with an HLB encompassing this range of HLBvalues.

Following this finding, a drug composition of the present invention wasprepared. First, 55 grams of topiramate, 30 grams of granular LUTROL F127, 11.5 grams of the polyethylene oxide (PEO) N80, and 3 grams ofpolyvinyl pyrrolidone (PVP) 2932 were passed through a #40 mesh sieveand the composition was dry mixed to a uniform blend wherein the PVPacts as a binder and the PEO acts as the structural polymer (carrier).The molecular weight of the polyethylene oxide was 200,000 grams permole and the molecular weight of the polyvinyl pyrrolidone wasapproximately 10,000. The polyoxyethylene oxide serves as carrier andstructural polymer 32. The polyvinyl pyrrolidone serves as the druglayer binder 36. The dry mixture was then wetted with anhydrous ethylalcohol SDA 3A anhydrous and stirred to form a uniformly wetted mass.The wet mass was then passed through a 20-mesh sieve, forming dampnoodles. The noodles were air dried at ambient conditions overnight,then passed again through a #20 mesh sieve, forming free-flowinggranules. Finally, 0.5 grams of drug layer lubricant 34 magnesiumstearate was passed through a # 60 mesh sieve over the granules andtumble mixed into the granules. This formed the drug compositiongranulation.

A push layer granulation was prepared in a similar manner. First, 89grams of polyethylene oxide 303, 7 grams of sodium chloride, and 3 gramsof hydroxypropyl methylcellulose E5 were passed through a #40 mesh sieveand dry mixed. The polyethylene oxide had a molecular weight ofapproximately 7,000,000 and the hydroxypropyl methylcellulose had amolecular weight of approximately 11,300. The polyethylene oxide servedas the push layer osmopolymer 41 and the hydroxypropyl methylcelluloseprovided the push layer binder 43. Next, the dry mixture was wetted withanhydrous ethyl alcohol SDA 3A and mixed to a uniform damp mass. Themass was passed through a #20 mesh sieve forming noodles that were airdried overnight. Next, the noodles were passed again through a #20 meshsieve forming free-flowing granules. Finally, 0.5 grams of minus #60mesh magnesium stearate, push layer lubricant 44, was tumbled into theblend. This formed the push layer granulation.

A portion of the drug composition granulation weighing 182 mg was filledinto a 3/16 inch diameter die cavity and lightly tamped with 3/16 inchbiconvex round tablet tooling. Then, 60 mg of the push layer granulationwas filled into the die and compressed and laminated to the drug layerusing a force of 0.5 tons with a Carver press. Six of these bi-layertablets were compressed.

Next, the tablets were coated with three layers. First, a solution wasprepared by dissolving 57 grams of hydroxyethyl cellulose 250 L and 3grams of polyethylene glycol in 940 grams of de-ionized water. Thehydroxyethyl cellulose had a molecular weight of approximately 90,000and the polyethylene glycol had a molecular weight of 3,350. This formeda smoothing coat solution to provide a smooth coatable surface forsubsequent coatings.

The six active tablets were mixed into a tablet bed of placebo tabletsthat weighed 0.5 kg. The tablet bed was coated with the smoothing coatsolution in an Aeromatic coater. The solution was applied in a currentof warm, dry air until about 4 mg of coating weight was accumulated oneach active tablet. The coating solution was stirred continuously duringthe coating process. The resulting smoothing coat produced a smoothtablet substrate and rounded the corners of the tablets. The resultingsmooth tablets were dried in a 40° C. force air oven overnight. (Thissmoothing coat is optional and is especially useful to round the cornersof the tablets where tablet lands have flash from the compressionprocess.)

The next coating solution was prepared by dissolving 269.5 grams ofethyl cellulose 100 cps, 196.0 grams of hydroxypropyl cellulose EFX, and24.5 grams of MYRJ 52 in 6510 grams of anhydrous ethanol SDA3A withstirring and warming. The ethyl cellulose had a molecular weight ofapproximately 220,000 and the hydroxypropyl cellulose had a molecularweight of approximately 80,000. The solution was allowed to stand atambient temperature. This formed the membrane subcoat solution.

The smooth tablets from above were mixed into a bed of placebo tabletsweighing 1.2 kg and the resulting mixed bed was charged into a VectorLDCS pan coater fitted with a 14 inch diameter coating pan. The membranesubcoat solution was then sprayed onto the bed of tablets in the coaterin a current of warm air. The coating solution was stirred continuouslyduring the process. The solution was applied in this manner until about5.5 mils of coating was accumulated on each drug tablet.

Then, 175 grams of cellulose acetate 398-10 and 75 grams of LUTROL F68were dissolved in 4,750 grams of acetone with warming and stirring. Thecellulose acetate had an average acetyl content of about 39.8 weightpercent and a molecular weight of approximately 40,000. This formed themembrane overcoat solution.

This membrane overcoat solution was applied to the bed of active andplacebo cores in the LDCS pan coater until 5 mils of membrane overcoataccumulated on each drug tablet. The three-coated layers formed wall 20of the present invention. An exit orifice 60 was mechanically drilledthrough the three coating layers on the drug layer side of the tabletsusing a 40 mil diameter drill bit and drill press. The systems were thendried in a forced air oven at 40° C. to remove residual processingsolvents.

The resulting six dosage forms (systems) were tested for release of drugas a function of time in de-ionized water at 37° C. by sampling every 2hours over a duration of 24 hours. Drug release was monitored withrefractive index chromatography. The drug 31 was delivered at anascending release pattern for 12-14 hours. The time to deliver 90% ofthe 100 mg dose was about 18 hours. The cumulative delivery at 24 hourswas 97.5%. The membranes were intact throughout the delivery pattern.

The dosage forms were sufficiently small to easily be swallowed by apatient even with the high drug loading of 55% present in the drugcomposition 30.

Similar dosage forms with push layers were formulated with 55% drug inthe drug composition, but without the solubilizing surfactant in anattempt to implement prior art technology. These dosage forms of theprior art were not operational. The drug compositions representing theprior art did not solublize the drug and resulted in drug compositionsthat could not be pumped from the dosage forms. The membranes of thesedosage forms split open in situ during in vitro testing, dumping thebolus of drug in an uncontrolled fashion. The splitting of the dosageforms was due to the strain induced within the membrane by the swellingpressure generated by the push layer pushing against the insoluble drugcomposition through the narrow 40 mil port.

Example 12 Bi-Layered Topiramate Dosage Form

A drug composition of 9.0 grams of micronized LUTROL F 127 was dry mixedwith 16.5 grams of topiramate. The topiramate had a nominal particlesize of 80 microns. Next, 3.45 grams POLYOX N80 and 0.9 grams ofpolyvinyl pyrrolidone were sieved through a minus 40 mesh and blendedinto the mixture. Then, 5 grams of anhydrous ethanol was added slowlywith stirring to form a damp mass. The damp mass was passed through a#16 mesh sieve and air dried overnight at ambient temperature. Theresulting dried noodles were passed again through #16 mesh sieve. Then,150 mg of magnesium stearate was passed through a #60 mesh sieve overthe dried granules and tumble mixed into the granules. The concentrationof surfactant in this drug composition granulation was 30 weightpercent.

The push layer granulation was prepared by passing 63.67 grams of POLYOX303, 30 grams of sodium chloride, and 5 grams of hydroxypropylmethylcellulose through a #40 mesh sieve and dry mixing to form auniform blend. Then, 1.0 gram of ferric oxide red was passed though a#60 mesh sieve into the mixture. The resulting mixture was wet massed byslowly adding anhydrous ethyl alcohol SDA3A anhydrous with stirring toform a uniformly damp mass. The mass was passed through a # 20 meshsieve, resulting in noodles that were dried at 40° C. in forced airovernight. The dried noodles were passed through a # 16 mesh sieve toform free-flowing granules. Finally, 25 mg of magnesium stearate and 8mg of butylated hydroxytoluene were sieved through a # 80 mesh sieveinto the granules and tumble mixed.

A portion of the drug composition granulation weighing 182 mg was filledinto a round 3/16-inch diameter die and lightly compressed with3/16-inch concave punches. Then, 60 mg of the push layer granulation wasadded to the drug layer and the two layers were laminated with a forceof 800 pounds. Six tablets were made.

The tablets were coated as described in Example 11 with 5 mg of thesmoothing coat, 5.4 mils of the subcoat membrane, and 5.7 mils of theovercoat membrane. One exit port of 40 mils diameter was drilled throughthe three coating layers and the systems were dried overnight at 40° C.in forced air.

The resulting dosage forms were tested as described in Example 11. Thesystems released 99% of the drug over a 24 hour duration. The releaserate was substantially ascending during the first 14 hours over whichtime about 76% of the drug was released. The system released about 90%of the drug over 19 hours. The final system was of the same size that isconvenient and feasible for patients in need to swallow as described inExample 11.

Example 13 Bi-Layered Topiramate Dosage Forms

Systems were made as described in Example 12 except that the surfactant33 comprised a blend of two solubilizing surfactants. The drugcomposition granulation was made according to the procedure in Example 2except that the surfactant consisted of 15 weight percent micronizedLUTROL F127 and 15 weight percent MYRJ 52 substituted for the 30 weightpercent micronized LUTROL F127. The weighted average HLB value of thetwo surfactants yielded an HLB value of 19.5, that is mid point betweenthe two HLB values of the single surfactants.

The dosage forms delivered at a substantially zero order rate betweenhour 2 and hour 14. The dosage forms released 89% of the dose over 24hours.

Example 14 Bi-Layered Topiramate Dosage Forms

Dosage forms were made as described in Example 13 but with a largerweight of the push layer. The push layer weight was 90 mg substitutedfor the 60 mg weight of the systems in Example 13.

The system delivered at a substantially ascending release rate for about12 hours. After 12 hours, the rate became descending. The amount of drugdelivered over 24 hours was about 93%.

Example 15 Bi-Layered Topiramate Dosage Form

A drug composition 30 was formed consisting of 30 wt. % drug topiramate,56 wt % surfactant LUTROL F127, 10 wt % carrier POLYOX N80 and 3 wt% PVPK2932 and 2 wt % stearic acid by wet granulating with anhydrous ethanol.

A push layer consisting of 63.37 wt % POLYOX 303 (7,000,000 molecularweight), 30 wt % NaCl, 5 wt% HPMC E5, 1 wt % Ferric Oxide, 0.5 wt % MgStearate and 0.08 wt % BHT was wet granulated with anhydrous ethanol.

Tablets with 333 mg of the drug composition (100 mg topiramate) and 133mg push layer were compressed using a 9/32″ longitudinally compressedtablet tooling. Total tablet (capsule shape) weight was 466 mg. Thesystems were coated, drilled, and dried according to the proceduresdescribed in Example 11. The systems were then tested for release ofdrug, producing a substantially zero order release pattern, deliveringthe drug at a steady rate of about 5.8 mg per hour over about 16 hours.

Example 16 Topiramate Capsule Shaped Tri-layer 100 mg System

A first drug composition was prepared as follows. First, 3000 g oftopiramate, 2520 g of polyethylene oxide with average molecular weightof 200,000 and 3630 g of poloxamer 407 (LUTROL F127) having an averagemolecular weight of 12,000 were added to a fluid bed granulator bowl.Next two separate binder solutions, a poloxamer binder solution and apolyvinylpyrrolidone identified as K29-32 having an average molecularweight of 40,000 binder solution were prepared by dissolving 540 g ofthe same poloxamer 407 (LUTROL F127) in 4860 g of water and 495 g of thesame polyvinylpyrrolidone in 2805 of water, respectively. The drymaterials were fluid bed granulated by first spraying with 2700 g of thepoloxamer binder solution and followed by spraying 2000 g of thepolyvinylpyrrolidone binder solution. Next, the wet granulation wasdried in the granulator to an acceptable moisture content 0.3%, andsized using by passing through a 7-mesh screen. Next, the granulationwas transferred to a blender and mixed with 5 g of butylatedhydroxytoluene as an antioxidant and lubricated with 200 g of stearicacid and 75 g of magnesium stearate.

A second drug composition was prepared as follows. First, 4000 g oftopiramate, 213 g of polyethylene oxide with average molecular weight of200,000, 4840 g of poloxamer 407 (LUTROL F127) having an averagemolecular weight of 12,000 and 10 g of ferric oxide, black were added toa fluid bed granulator bowl. Next, two separate binder solutions, apoloxamer binder solution and a polyvinylpyrrolidone identified asK29-32 having an average molecular weight of 40,000 binder solution wereprepared by dissolving 720 g of the same poloxamer 407 in 6480 g ofwater and 495 g of the same polyvinylpyrrolidone in 2805 of water,respectively. The dry materials were fluid bed granulated by firstspraying with 3600 g of the poloxamer binder solution and followed byspraying 2000 g of the polyvinylpyrrolidone binder solution. Next, thewet granulation was dried in the granulator to an acceptable moisturecontent, and sized by passing through a 7-mesh screen. Next, thegranulation was transferred to a blender and mixed with 2 g of butylatedhydroxytoluene as an antioxidant and lubricated with 200 g of stearicacid and 75 g of magnesium stearate.

Next, a push clayer was prepared as follows. First, a binder solutionwas prepared. 7.5 kg of polyvinylpyrrolidone identified as K29-32 havingan average molecular weight of 40,000 was dissolved in 50.2 kg of water.Then, 37.5 kg of sodium chloride and 0.5 kg of ferric oxide were sizedusing a Quadro Comil with a 21-mesh screen. Then, the screened materialsand 80.4 kg of polyethylene oxide (approximately 7,000,000 molecularweight) were added to a fluid bed granulator bowl. The dry materialswere fluidized and mixed while 48.1 kg of binder solution was sprayedfrom 3 nozzles onto the powder. The granulation was dried in thefluid-bed chamber to an acceptable moisture level, 0.5%. The coatedgranules were sized using a Fluid Air mill with a 7-mesh screen. Thegranulation was transferred to a tote tumbler, mixed with 63 g ofbutylated hydroxytoluene and lubricated with 310 g stearic acid.

Next, the first and second drug compositions and the push layer werecompressed into tri-layer tablets on multilayer Korsch press. First, 120mg of the first drug composition was added to the die cavity andpre-compressed, then, 160 mg of the second drug composition was added tothe die cavity and pre-compressed again, and finally, the push layer wasadded to achieve the total system weight of 480 mg and the layers werepressed into a ¼″ diameter, capsule shaped, deep concave, tri-layerarrangement.

The tri-layer arrangements were coated with bi-layer polymer membranelaminate in which the first coating layer was a rigid yet waterpermeable laminate and the second coating layer was a semi-permeablemembrane laminate. The first membrane laminate composition comprised 55%ethylcellulose, 45% hydroxylpropyl cellulose and 5% POLYOXYL.40 stearate(PEG 40 stearate or MYRJ 52S). The membrane-forming composition wasdissolved in 100% ethyl alcohol to make a 7% solids solution. Themembrane-forming composition was sprayed onto and around the tri-layerarrangements in a 10 kg scale pan coater until about 45 mg of membranewas applied to each tablet.

Next, the tri-layer arrangements coated with the first membrane laminatewere coated with the semi-permeable membrane. The membrane formingcomposition comprised 80% cellulose acetate having a 39.8% acetylcontent and 20% poloxamer 188 (PLURONIC F68 or LUTROL F68). Themembrane-forming composition was dissolved in 100% acetone solvent tomake a 5% solids solution. The membrane-forming composition was sprayedonto and around the tri-layer arrangements in a pan coater until about35 mg of membrane was applied to each tablet.

Next, one 40 mil (1 mm) exit passageway was laser drilled through thebi-layer membrane laminate to connect the drug layer with the exteriorof the dosage system. The residual solvent was removed by drying for 72hours at 40° C. and ambient humidity.

Next, the drilled and dried systems were color overcoated. The colorovercoat was a 12% solids suspension of OPADRY in water. The colorovercoat suspension was sprayed onto the tri-layer systems until anaverage wet coated weight of about 25 mg per system was achieved.

Next, the color-overcoated systems were clear coated. The clear coat wasa 5% solids solution of OPADRY in water. The clear coat solution wassprayed onto the color coated cores until an average wet coated weightof about 10 mg per system was achieved.

The dosage form produced by this manufacture were designed to deliver100 mg of topiramate in a substantially ascending rate of release atcertain controlled-delivery rate from the core containing the first drugcomposition of 30% topiramate, 25.2% polyethylene oxide possessing a200,000 molecular weight, 39% poloxamer 407 (LUTROL F127), 3%polyvinylpyrrolidone possessing a 40,000 molecular weight, 0.05%butylated hydroxytoluene, 2% stearic acid and 0.75% magnesium stearate,and the second drug composition of 40% topiramate, 2.13% polyethyleneoxide possessing a 200,000 molecular weight, 52% poloxamer 407 (LUTROLF127), 3% polyvinylpyrrolidone possessing a 40,000 molecular weight,0.1% black ferric oxide, 0.05% butylated hydroxytoluene, 2% stearic acidand 0.75% magnesium stearate. The push layer was comprised 64.3%polyethylene oxide comprising a 7,000,000 molecular weight, 30% sodiumchloride, 5% polyvinylpyrrolidone possessing an average molecular weightof 40,000, 0.4% ferric oxide, 0.05% butylated hydroxytoluene (BHT), and0.25% stearic acid. The bi-layer membrane laminate in which the firstmembrane layer was comprised of 55% ethylcellulose, 45% hydroxylpropylcellulose and 5% POLYOXYL 40 stearate (PEG 40 stearate or MYRJ 52S), andthe second membrane laminate was a semi-permeable wall which wascomprised of 80% cellulose acetate of 39.8% acetyl content and 20%poloxamer 188 (PLURONIC F68 or LUTROL F68). The dosage form comprisedone passageway, 40 mils (1 mm) on the center of the drug side. The finaldosage form contained a color overcoat and a clear overcoat.

The final dosage forms released such that about 90% of the drug wasrelease with a substantially ascending rate of release over about 16hours.

Example 17 Topiramate Capsule Shaped Tri-layer 12.5 mg System

A dosage form was manufactured as follows beginning with the first drugcomposition. First, 4 g of topiramate, 40 g of polyethylene oxide withaverage molecular weight of 200,000, 4 g of poloxamer 407 (LUTROL F127)having an average molecular weight of 12,000 and 1.5 g ofpolyvinylpyrrolidone identified as K29-32 having an average molecularweight of 40,000 were added to a beaker or mixing bowl. Next, the drymaterials were mixed for 60 seconds. Then 16 mL of denatured anhydrousalcohol was slowly added to blended materials with continuous mixing forabout 2 minutes. Next, the freshly prepared wet granulation was allowedto dry at room temperature for about 16 hours, and passed through a16-mesh screen. Next, the granulation were transferred to an appropriatecontainer, mixed and lubricated with 0.5 g of stearic acid.

Next, the second drug composition was prepared as follows: 6 g oftopiramate, 35.95 g of polyethylene oxide with average molecular weightof 200,000, 6 g of poloxamer 407 (LUTROL F127) having an averagemolecular weight of 12,000, 1.5 g of polyvinylpyrrolidone identified asK29-32 having an average molecular weight of 40,000 and 0.05 g of ferricoxide were added to a beaker or mixing bowl. Next, the dry materialswere mixed for 60 seconds. Then 16 mL of denatured anhydrous alcohol wasslowly added to blended materials with continuous mixing for about 2minutes. Next, the freshly prepared wet granulation was allowed to dryat room temperature for about 16 hours, and passed through a 16-meshscreen. Next, the granulation were transferred to an appropriatecontainer, mixed and lubricated with 0.5 g of stearic acid.

Next, a push layer was prepared as follows. First, a binder solution wasprepared. 7.5 kg of polyvinylpyrrolidone identified as K29-32 having anaverage molecular weight of 40,000 was dissolved in 50.2 kg of water.Then, 37.5 kg of sodium chloride and 0.5 kg of ferric oxide were sizedusing a Quadro Comil with a 21-mesh screen. Then, the screened materialsand 80.4 kg of polyethylene oxide (approximately 7,000,000 molecularweight) were added to a fluid bed granulator bowl. The dry materialswere fluidized and mixed while 48.1 kg of binder solution was sprayedfrom 3 nozzles onto the powder. The granulation was dried in thefluid-bed chamber to an acceptable moisture level, 0.5%. The coatedgranules were sized using a Fluid Air mill with a 7-mesh screen. Thegranulation was transferred to a tote tumbler, mixed with 63 g ofbutylated hydroxytoluene and lubricated with 310 g stearic acid.

Next, the first and second drug compositions and the push layer werecompressed into tri-layer tablets on the Carver Tablet Press. First, 56mg of the first drug composition was added to the die cavity andpre-compressed, then, 67 mg of the second drug composition was added tothe die cavity and pre-compressed again, and finally, the push layer wasadded to achieve the total system weight of 211 mg and the layers werepressed into a 3/16″ diameter capsule, deep concave, tri-layerarrangement.

The tri-layer arrangements were coated with bi-layer polymer membranelaminate in which the first coating layer was a rigid yet waterpermeable laminate and the second coating layer was a semi-permeablemembrane laminate. The coating was performed on a 10 kg scale pan coaterby spike-loading the topiramate tri-layer systems with the placebotablets. The first membrane laminate composition comprised 55%ethylcellulose, 45% hydroxylpropyl cellulose and 5% POLYOXYL 40 stearate(PEG 40 stearate or MYRJ 52S). The membrane-forming composition wasdissolved in 100% ethyl alcohol to make a 7% solids solution. Themembrane-forming composition was sprayed onto and around the tri-layerarrangements in a pan coater until about 30 mg of membrane was appliedto each tablet.

Next, the tr-ilayer arrangements coated with the first membrane laminatewere coated with the semi-permeable membrane. The membrane formingcomposition comprised 80% cellulose acetate having a 39.8% acetylcontent and 20% poloxamer 188 (PLURONIC F68 or LUTROL F68). Themembrane-forming composition was dissolved in 100% acetone solvent tomake a 5% solids solution. The membrane-forming composition was sprayedonto and around the tri-layer arrangements in a pan coater until about25 mg of membrane was applied to each tablet.

Next, one 30 mil (0.76 mm) exit passageway was laser drilled through thebi-layer membrane laminate to connect the drug layer with the exteriorof the dosage system. The residual solvent was removed by drying for 72hours at 40° C. and ambient humidity.

Next, the drilled and dried systems were color overcoated. The colorovercoat was a 12% solids suspension of OPADRY in water. The colorovercoat suspension was sprayed onto the tri-layer systems until anaverage wet coated weight of about 15 mg per system was achieved.

The dosage form produced by this manufacture was designed to deliver12.5 mg of topiramate in a substantially ascending rate of release atcertain controlled-delivery rate from the core containing the first drugcomposition of 8% topiramate, 80% polyethylene oxide possessing a200,000 molecular weight, 8% poloxamer 407 (LUTROL F127), 3%polyvinylpyrrolidone possessing a 40,000 molecular weight and 1% stearicacid, and the second drug composition of 12% topiramate, 71.9%polyethylene oxide possessing a 200,000 molecular weight, 12% poloxamer407 (LUTROL F127), 3% polyvinylpyrrolidone possessing a 40,000 molecularweight, 0.1% ferric oxide and 1% stearic acid. The push layer wascomprised of 64.3% polyethylene oxide comprising a 7,000,000 molecularweight, 30% sodium chloride, 5% polyvinylpyrrolidone possessing anaverage molecular weight of 40,000, 0.4% ferric oxide, 0.05% butylatedhydroxytoluene (BHT), and 0.25% stearic acid. The bi-layer membranelaminate in which the first membrane layer was comprised of 55%ethylcellulose, 45% hydroxylpropyl cellulose and 5% POLYOXYL 40 stearate(PEG 40 stearate or MYRJ 52S), and the second membrane laminate was asemi-permeable wall which was comprised of 80% cellulose acetate of39.8% acetyl content and 20% poloxamer 188 (PLURONIC F68 or LUTROL F68).The dosage form comprised one passageway, 30 mils (0.76 mm) on thecenter of the drug side. The final dosage form could contained a colorovercoat and a clear overcoat.

The final dosage form release topiramate such that about 90% of the drugwas release with a substantially ascending rate of release over about 16hours.

Example 18 Topiramate Capsule Shaped Bi-layer 100 mg System

A dosage form was manufactured as follows. First, 2880 g of topiramate,958 g of polyethylene oxide with average molecular weight of 200,000 and4980 g of poloxamer 407 (LUTROL F127) having an average molecular weightof 12,000 were added to a fluid bed granulator bowl. Next two separatebinder solutions, a poloxamer binder solution and a polyvinylpyrrolidoneidentified as K29-32 having an average molecular weight of 40,000 bindersolution were prepared by dissolving 500 g of the same poloxamer 407(LUTROL F127) in 4500 g of water and 750 g of the samepolyvinylpyrrolidone in 4250 of water, respectively. The dry materialswere fluid bed granulated by first spraying with 3780 g of the poloxamerbinder solution and followed by spraying 3333 g of thepolyvinylpyrrolidone binder solution. Next, the wet granulation wasdried in the granulator to an acceptable moisture content, 0.5%, andsized using by passing through a 7-mesh screen. Next, the granulationwas transferred to a blender and mixed with 2 g of butylatedhydroxytoluene (BHT) as an antioxidant and lubricated with 200 g ofstearic acid and 100 g of magnesium stearate.

Next, a push layer was prepared as follows. First, a binder solution wasprepared. 7.5 kg of polyvinylpyrrolidone identified as K29-32 having anaverage molecular weight of 40,000 was dissolved in 50.2 kg of water.Then, 37.5. kg of sodium chloride and 0.5 kg of ferric oxide were sizedusing a Quadro Comil with a 21-mesh screen. Then, the screened materialsand 80.4 kg of polyethylene oxide (approximately 7,000,000 molecularweight) were added to a fluid bed granulator bowl. The dry materialswere fluidized and mixed while 48.1 kg of binder solution was sprayedfrom 3 nozzles onto the powder. The granulation was dried in thefluid-bed chamber to an acceptable moisture level. The coated granuleswere sized using a Fluid Air mill with a 7-mesh screen. The granulationwas transferred to a tote tumbler, mixed with 63 g of butylatedhydroxytoluene and lubricated with 310 g stearic acid.

Next, the drug composition and the push composition were compressed intobi-layer tablets on multilayer Korsch press. First, 278 mg of the drugcomposition was added to the die cavity and pre-compressed, then, thepush composition was added to achieve the total system weight of 463 mgand the layers were pressed into a 15/64″ diameter, capsule shaped, deepconcave, bi-layer arrangement.

The bi-layer arrangements were coated with bi-layer polymer membranelaminate in which the first coating layer was a rigid yet waterpermeable laminate and the second coating layer was a semi-permeablemembrane laminate. The first membrane laminate composition comprised 55%ethylcellulose, 45% hydroxylpropyl cellulose and 5% POLYOXYL 40 stearate(PEG 40 stearate or MYRJ 52S). The membrane-forming composition wasdissolved in 100% ethyl alcohol to make a 7% solids solution. Themembrane-forming composition was sprayed onto and around thearrangements in a pan coater until about 38 mg of membrane was appliedto each tablet.

Next, the bi-layer arrangements coated with the first membrane laminatewere coated with the semi-permeable membrane. The membrane formingcomposition comprised 80% cellulose acetate having a 39.8% acetylcontent and 20% poloxamer 188 (PLURONIC F68 or LUTROL F68). Themembrane-forming composition was dissolved in 100% acetone solvent tomake a 5% solids solution. The membrane-forming composition was sprayedonto and around the arrangements in a pan coater until about 30 mg ofmembrane was applied to each tablet.

Next, one 45 mil (1.14 mm) exit passageway was laser drilled through thebi-layer membrane laminate to connect the drug layer with the exteriorof the dosage system. The residual solvent was removed by drying for 72hours at 40° C. and ambient humidity.

Next, the drilled and dried dosage forms were coated with an immediaterelease drug overcoat. The drug overcoat was a 13% solids aqueoussolution containing 780 g of topiramate, 312 g of coPOVIDONE (KOLLIDONEVA 64) and 208 g of hydroxypropyl methycellulose possessing an averagemolecular weight of 11,200. The drug overcoat solution as sprayed ontothe dried coated cores until an average wet coated weight of about 33 mgper system was achieved.

Next, the drug-over coated systems were color over coated. The colorovercoat was a 12% solids suspension of OPADRY in water. The colorovercoat suspension was sprayed onto the drug over coated systems untilan average wet coated weight of about 25 mg per system was achieved.

Next, the color-over coated systems were clear coated. The clear coatwas a 5% solids solution of OPADRY in water. The clear coat solution assprayed onto the color coated cores until an average wet coated weightof about 25 mg per system was achieved.

The dosage form produced by this manufacture was designed to deliver 20mg of topiramate as an immediate release from an overcoat comprised of60% topiramate, 24% co-POVIDONE and 16% hydroxypropyl methylcellulosefollowed by the controlled delivery of 80 mg of topiramate from the drugcomposition containing 28.8% topiramate, 9.58% polyethylene oxidepossessing a 200,000 molecular weight, 53.6% poloxamer 407 (LUTROLF127), 5% polyvinylpyrrolidone possessing a 40,000 molecular weight,0.02% butylated hydroxytoluene (BHT), 2% stearic acid and 1% magnesiumStearate. The push layer was comprised 64.3% polyethylene oxidecomprising a 7,000,000 molecular weight, 30% sodium chloride, 5%polyvinylpyrrolidone possessing an average molecular weight of 40,000,0.4% ferric oxide, 0.05% butylated hydroxytoluene, and 0.25% stearicacid. The bi-layer membrane laminate in which the first membrane layerwas comprised of 55% ethylcellulose, 45% hydroxylpropyl cellulose and 5%POLYOXYL 40 stearate (PEG 40 stearate or MYRJ 52S), and the secondmembrane laminate is a semi-permeable wall which was comprised of 80%cellulose acetate of 39.8% acetyl content and 20% poloxamer 188(PLURONIC F68 or LUTROL F68). The dosage form comprised one passageway,45 mils (1.14 mm) on the center of the drug side. The final dosage formcontained a color overcoat and a clear overcoat.

The final dosage form had a mean release rate of 6 mg topiramate perhour releasing the topiramate with a substantially zero-order rate orrelease.

Examples 19-24 Topiramate Dosage Forms

Tables 1-9 below list composition details for additional embodiments ofthe present invention. More particularly, the tables below providedetails on the composition of tri-layer, controlled release, osmoticdosage forms containing topiramate. Said dosage forms comprised two drugcompositions, wherein the amount and/or concentration of topiramate inthe two drug compositions was different, and a push layer.

Each of the dosage forms described below was prepared according to theprocedure described in Example 25, by selecting and substituting thesuitable components.

Table 1 below lists the components of dosage forms as a function oftotal dosage of topiramate. For each layer or coating, weights arelisted in milligrams (e.g for the drug layers, push layers,semi-permeable membranes, other coatings, etc.). Also listed in Table 1are the sizes for each dosage form, as prepared. TABLE 1 Dosage FormComponents Dosage 10 mg 20 mg 45 mg 90 mg 135 mg 180 mg Size (inches)3/16 15/64 3/16 15/64 17/64 9/32 Drug Layer 1 60 120 60 120 180 240 DrugLayer 2 60 120 60 120 180 240 Push Layer 90 180 90 180 270 360 Subcoat15 20 15 20 25 25 Membrane Coat (99:1 CA:poloxamer) 32 40 36 40 46 50Membrane Coat (78:22 CAB:poloxamer) 28 38 28 38 42 48CA = cellulose acetateCAB = cellulose acetate butyrate

Table 2 below lists the components and amounts used in the preparationof the first drug composition for dosage forms comprising 45-180 mgtotal of topiramate. Target % (wt/wt) in granulation is the weightpercent of the component as a function of the total weight of the druglayer. TABLE 2 First Drug Composition (45-180 mg Dosages) Target %(wt/wt) Material ID in Granulation Topiramate 32.00 Polyethylene Oxide,NF, N-80, 200K, TG, LEO 16.23 POVIDONE, USP, Ph Eur, (K29-32) 3.00Poloxamer 407, NF (Micronized) 42.00 Methylcellulose, USP, 15CPS,(A15-LV-PREMIUM) 2.50 Stearic Acid, NF, Ph Eur (Powder) 3.00 MagnesiumStearate, NF, Ph Eur 1.25 BHT, FCC, Ph Eur (Milled) 0.02

Table 3 below lists the components and amounts used in the preparationof the second drug composition for dosage forms comprising 45-180 mgtotal of topiramate. Target % (wt/wt) in granulation is the weightpercent of the component as a function of the total weight of the druglayer. TABLE 3 Second Drug Composition (45-180 mg Dosages) Target %(wt/wt) Material ID in Granulation Topiramate 43.00 POVIDONE, USP, PhEur, (K29-32) 3.00 Poloxamer 407, NF (Micronized) 49.90 Methylcellulose,USP, 15CPS, (A15-LV-PREMIUM) 2.50 Ferric Oxide, NF, (Yellow) 0.08Stearic Acid, NF, Ph Eur (Powder) 1.00 Magnesium Stearate, NF, Ph Eur0.50 BHT, FCC, Ph Eur (Milled) 0.02

Table 4 below lists the components and amounts used in the preparationof first drug composition for dosage forms comprising 10-20 mg total oftopiramate. Target % (wt/wt) in granulation is the weight percent of thecomponent as a function of the total weight of the drug layer. TABLE 4First Drug Composition (10-20 mg dosages) Target % (wt/wt) Material IDin Granulation Topiramate 5.00 Polyethylene Oxide, NF, N-80, 200K, TG,LEO 88.73 Poloxamer 407, NF (Micronized) 2.00 POVIDONE, USP, Ph Eur,(K29-32) 3.00 Stearic Acid, NF, Ph Eur (Powder) 1.00 Magnesium Stearate,NF, Ph Eur 0.25 BHT, FCC, Ph Eur (Milled) 0.02

Table 5 below lists the components and amounts used in the preparationof the second drug composition for dosage forms comprising 10-20 mgtotal of topiramate. Target % (wt/wt) in granulation is the weightpercent of the component as a function of the total weight of the druglayer. TABLE 5 Second Drug Composition (10-20 mg Dosages) Target %(wt/wt) Material ID in Granulation Topiramate 12.00 Polyethylene Oxide,NF, N-80, 200K, TG, LEO 71.72 Poloxamer 407, NF (Micronized) 12.00POVIDONE, USP, Ph Eur, (K29-32) 3.00 Iron Oxide, Red 0.01 Stearic Acid,NF, Ph Eur (Powder) 1.00 Magnesium Stearate, NF, Ph Eur 0.25 BHT, FCC,Ph Eur (Milled) 0.02

Table 6 below lists the components and amounts used in the preparationof the push layer for all dosage forms topiramate. Target % (wt/wt) ingranulation is the weight percent of the component as a function of thetotal weight of the drug layer. TABLE 6 Push Layer Composition Target %(wt/wt) Material ID in Granulation Polyethylene Oxide, NF, 303, 7000K,TG, LEO 64.3 Sodium Chloride, USP, Ph Eur, (Powder) 30.0 POVIDONE, USP,Ph Eur, (K29-32) 5.0 Ferric Oxide, NF, (Red) 0.1 Ferric Oxide, NF,(Yellow) 0.3 Stearic Acid, NF, Ph Eur, (Powder) 0.25 BHT, FCC, Ph Eur,(Milled) 0.05

Table 7 below lists the components and amounts used in the preparationof the subcoat (aqueous subcoat) for all dosage forms topiramate. Target% (wt/wt) in subcoat formulation is the weight percent of the componentas a function of the total weight of the subcoat. TABLE 7 SubcoatComposition Target % (wt/wt) in Material ID Subcoat FormulationHydroxyethyl Cellulose, NF 95 Polyethylene Glycol 3350, NF, Ph Eur, LEO5

Tables 8 and 9 below list the components and amounts used in thepreparation of the CAB (cellulose acetate butyrate) membrane coat andthe CA (cellulose acetate) membrane coat, respectively, for all dosageforms of topiramate. Target % (wt/wt) in subcoat formulation is theweight percent of the component as a function of the total weight of thesubcoat. TABLE 8 CAB Membrane Coat Target % (wt/wt) in Material IDSubcoat Formulation Cellulose Acetate Butyrate (171-15) 78 Poloxamer188, NF, Ph Eur 22

TABLE 9 CA Membrane Coat Target % (wt/wt) in Material ID SubcoatFormulation Cellulose Acetate, NF, (398-10) 99 Poloxamer 188, NF, Ph Eur1

Example 25 Large Scale Manufacture of Topiramate Dosage Forms

A push layer granulation was manufactured as follows. The composition ofthe push layer was as follows: 64.3% polyethylene oxide, 30% sodiumchloride, 5% POVIDONE, 0.4% ferric oxide, 0.25% stearic acid and 0.05%butylated hydroxytoluene.

A binder solution was prepared as follows: 7.5 kg of POVIDONE was addedto 50.2 kg of purified water in a mixing vessel and mixed until thePOVIDONE was completely in solution. The net weight of the preparedbinder solution was determined by weighing.

The dry ingredients—80.4 kg of polyethylene oxide, 37.5 kg of sodiumchloride and 0.5 kg of ferric oxide were charged into a tote. The fluidbed granulator was assembled with the guns required for spraying thebinder solution. The granulator was then warmed to an inlet airtemperature of 43-47° C. and 48 kg of the binder solution was meteredinto the granulator. After the spraying was completed, the granules wereallowed to dry in the granulator until a moisture content less than orequal to 1% was obtained. The dried granules were then milled through aGranumill using a 7 mesh screen. The milled granulation was weighed andcollected in a tote. 0.05% butylated hydroxytoluene by weight of thegranulation was added to the tote and the granulation was mixed for 5min. Stearic acid amount equivalent to 0.25% of the granulation wasweighed and added to the tote. The granules were then mixed for anadditional 5 minutes.

A granulation for the first drug composition was manufactured asfollows. The composition of the first drug composition was as follows:32% topiramate, 16.23% polyethylene oxide, 42% poloxamer407, 3%POVIDONE, 2.5% methylcellulose, 3% stearic acid, 1.25% magnesiumstearate and 0.02% butylated hydroxytoluene.

A binder solution was prepared as follows: 480 g of POVIDONE was addedto 4.32 kg of purified water in a mixing vessel and mixed until thePOVIDONE was completely in solution. The net weight of the preparedbinder solution was determined by weighing.

A methylcellulose granule coating solution was prepared as follows: 2.6kg of purified water was heated to a temperature greater than 50° C. 400g of methylcellulose is gradually added to the hot water while mixing.Mixing was continued until all solids were dispersed. 5 kg of purifiedwater was then added to the mixing vessel and mixing was continued untilall solids were dissolved. The net weight of prepared granule coatingsolution was determined by weighing.

The dry ingredients—3.2 kg topiramate, 1.623 kg polyethylene oxide, and4.2 kg poloxamer were charged into a tote. The fluid bed granulator wasassembled with the guns required for spraying the binder solution. Thegranulator was then warmed to an exhaust air temperature less than 25°C. and 3 kg of the binder solution was metered into the granulator.Following the spraying of the binder solution, 5 kg of granule coatingsolution was sprayed onto the granules. After spraying was completed,the granules were allowed to dry in the granulator until a moisturecontent less than or equal to 0.5% was obtained. The dried granulationwas then milled through a Granumill using a 7 mesh screen. The milledgranulation was weighed and collected in a tote. 0.05% butylatedhydroxytoluene by weight of the granulation was added to the tote andthe granulation was mixed for 5 min. Stearic acid amount equivalent to3% of the granulation was weighed and added to the tote. The granuleswere then mixed for an additional 5 minutes. Magnesium stearate amountequivalent to 1.25% of the granulation was weighed and added to thetote. The granules were then mixed for an additional 30 seconds.

A granulation for the second drug composition was manufactured asfollows. The composition of the second drug composition was as follows:43% topiramate, 49.9% poloxamer 407, 3% POVIDONE, 2.5% methylcellulose,1% stearic acid, 0.5% magnesium stearate, 0.08% yellow ferric oxide, and0.02% butylated hydroxytoluene.

A binder solution was prepared as follows: 480 g of POVIDONE was addedto 4.32 kg of purified water in a mixing vessel and mixed until thePOVIDONE was completely in solution. The net weight of the preparedbinder solution was determined by weighing.

A methylcellulose granule coating solution was prepared as follows: 2.6kg of purified water was heated to a temperature greater than 50° C. 400g of methylcellulose was gradually added to the hot water while mixing.Mixing was continued until all solids were dispersed. 5 kg of purifiedwater was then added to the mixing vessel and mixing was continued untilall solids are dissolved. The net weight of prepared granule coatingsolution was determined by weighing.

The dry ingredients—4.3 kg Topiramate, 4.9 kg poloxamer and 8 g ferricoxide were charged into a tote. The fluid bed granulator was assembledwith the guns required for spraying the binder solution. The granulatorwas then warmed to an exhaust air temperature less than 25° C. and 3 kgof the binder solution was metered into the granulator. Following thespraying of the binder solution, 5 kg of granule coating solution wassprayed onto the granules. After spraying was completed, the granuleswere allowed to dry in the granulator until a moisture content less thanor equal to 0.5% was obtained. The dried granulation was then milledthrough a Granumill using a 7 mesh screen. The milled granulation wasweighed and collected in a tote. 0.05% butylated hydroxytoluene byweight of the granulation was added to the tote and the granulation wasmixed for 5 min. Stearic acid amount equivalent to 1% of the granulationwas weighed and added to the tote. The granules were then mixed for anadditional 5 minutes. Magnesium stearate amount equivalent to 0.5% ofthe granulation was weighed and added to the tote. The granules werethen mixed for an additional 30 seconds.

Compression of cores was completed as follows. The above granulationswere compressed into a trilayer tablet core. Different weights werecompressed into different size cores for the various doses.

A trilayer tablet core to deliver 90 mg drug was compressed as follows:28.6% by weight of drug layer 1, 28.6% by weight of drug layer 2 and42.9% by weight of push layer were compressed to form a trilayer tableton a Korsch Tablet press. For the 90 mg tablet 120 mg drug layer 1, 120mg drug layer 2 and 180 mg push layer were compressed together using a15/64″ diameter tooling set.

Subcoat application was completed as follows. The composition of thesubcoat was as follows: 95% hydroxyethyl cellulose and 5% polyethyleneglycol 3350.

A subcoating solution was prepared as follows: 14.1 kg of water wasadded to a mixing vessel. 45 g of polyethylene glycol was added andmixed until all solids were dissolved. 855 g of hydroxyethyl cellulosewas weighed and charged to the PEG solution while mixing. Mixing wascontinued until all solids were dissolved. The net weight of theprepared subcoating solution was determined by weighing.

9 g of compressed cores was charged to a coater and the cores weretumbled in the coater until a target exhaust temperature of 32° C. wasachieved. The subcoating solution was applied to the cores while thecoater was rotated at 12 rpm. Coating was continued until the targetweight of 34 mg is achieved. At the end of the spray, the cores wereremoved from the coater.

The rate controlling membrane was completed as follows. The compositionof the rate controlling membrane was as follows: 99% cellulose acetateand 1% poloxamer 188.

A membrane coating solution was prepared as follows: 47 kg of acetonewas charged to a mixing vessel. The acetone was heated to 28° C. whilethe mixer was turned on. 25 g of poloxamer was added to the acetone andmixed until completely dissolved. 2.475 kg of cellulose acetate wasadded to the poloxamer solution, followed by addition of 475 g ofpurified water. The solution was mixed until all solids are in solution.The net weight of the prepared membrane coating solution was determinedby weighing.

9 kg of subcoated cores were charged to a coater and the cores weretumbled in the coated until a target exhaust temperature of 32° C. wasachieved. The membrane coating solution was applied to the cores whilethe coater was rotated at 12 rpm. Coating was continued until the targetweight of 36 mg was achieved. At the end of spray, the cores wereremoved from the coater.

The exit orifice was drilled and the dosage forms were then dried asfollows. A 1 mm orifice was drilled on the membrane coated cores using alaser drilling device. The drilled cores were then spread out on dryingtrays and dried at 40° C. at ambient humidity for up to 10 days.

Example 26 Topiramate Dosage Form

A drug core composition comprising 53.7 grams topiramate, 29.8 grams ofCRODESTA F160, 10 grams of polyethylene oxide N-80 and 6 grams ofpolyethylene pyrrolidone K90, at less than 40 mesh particle sizes, weredry blended for about 30 minutes. The dry blend was then wetted with 20grams of anhydrous ethyl alcohol SDA 3A while stirring to form ahomogenous wet dough. The wet dough was passed thru #20 stainless steelscreen to form noodles, and dried under a hood at ambient conditions forabout 12 hours (overnight). The dried noodles were passed thru #20stainless steel screen to form granules. These dried granules were thenlubricated with 0.5 grams of <60 mesh magnesium stearate by rollerblending for 3 minutes.

The push layer granulation was manufactured using the same processwherein 73.7 grams of polyethylene oxide 303, 20 grams of sodiumchloride, 5 grams of polyvinyl pyrrolidone K2932, 1 gram of ferric oxideand 0.05 gram of BHT were dry blended for 30 minutes. The dry blend wasthen wetted with 80 grams of anhydrous ethyl alchol SDA 3A whilestirring, to form a homogenous wet dough; The wet dough was then passedthru a #20 mesh stainless steel screen to form noodles. These noodleswere dried for about 12 hours under a hood at ambient conditions. Thedried noodles were then passed thru a #20 mesh stainless steel screen toform granules. These dried granules were then lubricated with 0.25 gramsof stearic acid by roller blending for 3 minutes.

Both the drug and push layers were used to form a bilayer core using a3/16-inch diameter LCT tooling. Drug layer granulation weighing 182 mgwas introduced into the die first and then after slight tamping, thepush layer granulation weighing 60 mg were then introduced and thencompressed with a Carver Press at 0.75 ton compression force. Thisprocedure was repeated until a desired amount of test tablets wereproduced. For initial trials 10 tablets were produced.

To these tablets, 3 layers of coating were applied. The first coating, asmoothing coating, provided a smooth surface for the succeedingrate-controlling membrane coatings. For the smoothing coating, 5 gramsof poloxamer 407 were dissolved in 783 grams of de-ionized water bystirring. Then 45 grams of hydroxyethyl cellulose were introduced intothe solution and stirred until a clear solution was achieved. AnAeromatic Coater was utilized for this coating. The 10 active tabletswere mixed with placebo tablets (fillers) to provide a coater load of500 grams. Standard Aeromatic Coating procedures were followed to coatabout 3 to 4 mg of coating on each active tablet. The coated activetablets were dried in an oven at 40° C. and ambient humidity for about12 hours.

The second coating was prepared by dissolving 77 grams of ethylcellulose(100 cps), 56 grams of hydroxypropyl cellulose EFX, and 7 grams of MYRJ52S in 4,527 grams of warm ethanol SDA3A while stirring. Stirring wasperformed until a homogeneous solution was achieved. After stirring, thesolution was sealed and stored at ambient conditions for about 2 daysbefore application. An LDCS Vector Pan Coater was used for this coating.To achieve a 1.2 kg coater load, the 10 smooth coated active tabletswere mixed with placebo filler tablets and coated with the secondcoating. Standard pan coating procedures were used for the coatingprocess with a target coat of about 6 mils.

For the third coating, 87.5 grams of cellulose acetate 398-10 and 37.5grams of LUTROL F68 were dissolved in 2,375 grams acetone with stirringand warming. This coating was applied using the same coater and standardcoating procedure as with the second coat. After coating the activetablets were manually drilled to produce a 40 mil orifice, and thendried in an oven at 40° C. and ambient humidity for about 12 hours(overnight).

Drug release rates and residuals were determined as described in Example11 from 5 of these tablets at intervals of 2 hours for 24 hours. Theresults show that topiramate was delivered at a substantially ascendingrate of release for 12-14 hours. The time to deliver 90% of the 100 mgdose was about 16 hours. The cumulative delivery at 24 hours was 99%.The membranes were intact throughout the delivery pattern.

Example 27 Topiramate Dosage Form

Using the same granulation procedure described in Example 26, above, thefollowing formulation consisting of 50 grams topiramate, 33.5 gramsCRODESTA F-160, 10 grams polyethylene oxide N-80, and 6 grams ofpolyvinyl pyrrolidone K90, was wet granulated and lubricated with 0.5gram and magnesium stearate. This constituted the drug layer with a loadof 33.5% surfactant. Tablets were made following the procedures andmaterials described in Example 26.

Drug release rates were determined as described in Example 11. Theresults show that topiramate was delivered at a substantially ascendingrate of release for 12-14 hours. The time to deliver 90% of the 100 mgdose was about 16 hours. The cumulative delivery at 24 hours was 99.5%.The membranes were intact throughout the delivery pattern.

Example 28 Topiramate Dosage Form

Tablets were made as described in Examples 26 and 27, but using a druglayer granulation consisting of 38.5% surfactant (CRODESTA F160). A pushlayer composition in the amount of 60 mg was used. Membrane compositionsand amounts applied were approximately the same as counterpart tabletsin Examples 26 and 27.

Drug release rates were determined on these tablets according to sameprocedures described in Example 11. The results show that topiramate wasdelivered at a substantially ascending rate of release for 14-16 hours.The time to deliver 90% of the 100 mg dose was about 17 hours. Thecumulative delivery at 24 hours was 98.7%. The membranes were intactthroughout the delivery pattern.

Example 29 Topiramate Dosage Form

Using standard procedures for fluid bed granulation, 288 grams oftopiramate, 536 grams of CRODESTA F-160, 95.8 grams of polyethyleneoxide N-80, and 5 grams of polyvinyl pyrrolidone were granulated. Thisgranulation was then lubricated with 2 grams of stearic acid and 1 gramof magnesium stearate. A Glatt Fluid Bed Granulator (1 kg) capacity wasutilized for this granulation.

To test if this granulation does or does not smear under manufacturingconditions, a tabletting run was performed with a multi-layer tabletpress (Korsch Multi-Layer Tablet Press). Using the same tablet press andparameters, another tabletting run was performed using a counterpartgranulation that contains poloxamer 407 as surfactant. It was observedthat no smearing on the turret table and on the punches was observedwith the granulation containing CRODESTA F160. In contrast; smearing wasobserved with the granulation containing poloxamer 407.

Therefore, the sugar ester surfactant provides an advantage informulating dosage forms with respect to the poloxamer surfactant, andthe sugar ester surfactant CRODESTA is another preferred surfactant fortopiramate in the present invention.

Examples 30-35 Topiramate Dosage Forms

Tables 10-17 below list composition details for additional embodimentsof the present invention. More particularly, the tables below providedetails on the composition of tri-layer, controlled release, osmoticdosage forms containing topiramate. Said dosage forms comprised two drugcompositions, wherein the amount and/or concentration of topiramate inthe two drug compositions was different, and a push layer.

Each of the dosage forms described below was prepared according to theprocedure described in Example 25, by selecting and substituting thesuitable components.

Table 10 below lists the components of dosage forms as a function oftotal dosage of topiramate. For each layer or coating, weights arelisted in milligrams (e.g for the drug layers, push layers,semi-permeable membranes, other coatings, etc.). Also listed in Table 1are the sizes for each dosage form, and the orifice sizes on the dosageform, as prepared. TABLE 10 Dosage Form Components Dosage 10 mg 20 mg 40mg 80 mg 120 mg 160 mg Size (inches) 3/16 15/64 3/16 15/64 17/64 9/32Drug Layer 1 40 80 60 120 180 240 Drug Layer 2 60 120 60 120 180 240Push Layer 90 150 100 180 270 330 Subcoat (Aqueous) 15 20 15 20 25 25Membrane Coat (99/1 CA/Poloxamer) 32 32 36 38 40 44 Orifice Size (mil) 1× 40 1 × 40 1 × 40 1 × 40 2 × 60 2 × 80CA = Cellulose Acetate

Table 11 below lists the components and amounts used in the preparationof the first drug composition for dosage forms comprising 40-160 mgtotal of topiramate. Target % (wt/wt) in granulation is the weightpercent of the component as a function of the total weight of the druglayer. TABLE 11 First Drug Composition (40-160 mg Dosages) Target %(wt/wt) Material ID in Granulation Topiramate 29.67 Polyethylene Oxide,NF, N-80, 200K, TG, LEO 33.06 Povidone, USP, Ph Eur, (K29-32) 2.00Poloxamer 407, NF (Micronized) 29.00 METHYLCELLULOSE, USP, 15CPS, 3.00(A15-LV-PREMIUM) Stearic Acid, NF, Ph Eur (Powder) 3.00 MagnesiumStearate, NF, Ph Eur 0.25 BHT, FCC, Ph Eur (Milled) 0.02

Table 12 below lists the components and amounts used in the preparationof the second drug composition for dosage forms comprising 45-180 mgtotal of topiramate. Target % (wt/wt) in granulation is the weightpercent of the component as a function of the total weight of the druglayer. TABLE 12 Second Drug Composition (40-160 mg Dosages) Target %(wt/wt) Material ID in Granulation Topiramate 37.00 Povidone, USP, PhEur, (K29-32) 2.00 Poloxamer 407, NF (Micronized) 54.65 METHYLCELLULOSE,USP, 15CPS, 3.00 (A15-LV-PREMIUM) Ferric Oxide, NF, (Yellow) 0.08Stearic Acid, NF, Ph Eur (Powder) 3.00 Magnesium Stearate, NF, Ph Eur0.25 BHT, FCC, Ph Eur (Milled) 0.02

Table 13 below lists the components and amounts used in the preparationof the first drug composition for dosage forms comprising 10-20 mg totalof topiramate. Target % (wt/wt) in granulation is the weight percent ofthe component as a function of the total weight of the drug layer. TABLE13 First Drug Composition (10-20 mg dosages) Target % (wt/wt) MaterialID in Granulation Topiramate 6.25 Polyethylene Oxide, NF, N-80, 200K,TG, LEO 80.48 Poloxamer 407, NF (Micronized) 10.00 Povidone, USP, PhEur, (K29-32) 2.00 Stearic Acid, NF, Ph Eur (Powder) 1.00 MagnesiumStearate, NF, Ph Eur 0.25 BHT, FCC, Ph Eur (Milled) 0.02

Table 14 below lists the components and amounts used in the preparationof the second drug composition for dosage forms comprising 10-20 mgtotal of topiramate. Target % (wt/wt) in granulation is the weightpercent of the component as a function of the total weight of the druglayer. TABLE 14 Second Drug Composition (10-20 mg Dosages) Target %(wt/wt) Material ID in Granulation Topiramate 12.50 Polyethylene Oxide,NF, N-80, 200K, TG, LEO 69.22 Poloxamer 407, NF (Micronized) 15.00Povidone, USP, Ph Eur, (K29-32) 2.00 Iron Oxide, Red 0.01 Stearic Acid,NF, Ph Eur (Powder) 1.00 Magnesium Stearate, NF, Ph Eur 0.25 BHT, FCC,Ph Eur (Milled) 0.02

Table 15 below lists the components and amounts used in the preparationof the push layer for all dosage forms of topiramate. Target % (wt/wt)in granulation is the weight percent of the component as a function ofthe total weight of the drug layer. TABLE 15 Push Layer CompositionTarget % (wt/wt) Material ID in Granulation Polyethylene Oxide, NF, 303,7000K, TG, LEO 74.30 Sodium Chloride, USP, Ph Eur, (Powder) 20.00Povidone, USP, Ph Eur, (K29-32) 5.00 Ferric Oxide, NF, (Red) 0.10 FerricOxide, NF, (Yellow) 0.30 Stearic Acid, NF, Ph Eur, (Powder) 0.25 BHT,FCC, Ph Eur, (Milled) 0.05

Table 16 below lists the components and amounts used in the preparationof the subcoat (aqueous subcoat) for all dosage forms of topiramate.Target % (wt/wt) in subcoat formulation is the weight percent of thecomponent as a function of the total weight of the subcoat. TABLE 16Subcoat Composition Target % (wt/wt) in Material ID Subcoat FormulationHydroxyethyl Cellulose, NF 95 Polyethylene Glycol 3350, NF, Ph Eur, LEO5

Tables 17 below lists the components and amounts used in the preparationof the CA (cellulose acetate) membrane coat, for all dosage forms oftopiramate. Target % (wt/wt) in subcoat formulation is the weightpercent of the component as a function of the total weight of thesubcoat. TABLE 17 CA Membrane Coat Target % (wt/wt) in Material IDSubcoat Formulation Cellulose Acetate, NF, (398-10) 99 Poloxamer 188,NF, Ph Eur 1

In as much as the foregoing specification comprises disclosedembodiments, it is understood what variations and modifications may bemade herein, in accordance with the principles disclosed, withoutdeparting from the invention.

1. A drug formulation comprising granules having a substrate and acoating, said granule substrate comprising a solubilizing agent or a lowsolubility therapeutic drug, or both, and said granule coatingcomprising a hydrophilic polymer.
 2. A drug formulation as in claim 1,wherein the granule substrate comprises a solubilizing agent.
 3. A drugformulation as in claim 2, wherein the solubilzing agent is asurfactant.
 4. A drug formulation as in claim 3, wherein the granulesubstrate comprises a low solubility therapeutic drug.
 5. A drugformulation as in claim 4, wherein the low solubility therapeutic drugis topiramate.
 6. A drug formulation as in claim 4, wherein the amountof surfactant is between about 5% and about 50% by weight of the core.7. A drug formulation as in claim 4, wherein the surfactant is selectedfrom the group consisting of polyoxyl 40 stearate, polyoxyl 50 stearate,triblock co-polymers of ethylene oxide/propylene oxide/ethylene oxide,sorbitan monopalmitate, sorbitan monostearate, glycerol monostearate,polyoxyethlene stearate, polyoxyethylene 40 sorbitol lanolin derivative,polyoxyethylene 75 sorbitol lanolin derivative, polyoxyethylene 6sorbitol beeswax derivative, polyoxyethylene 20 sorbitol beeswaxderivative, polyoxyethylene 20 sorbitol lanolin derivative,polyoxyethylene 50 sorbitol lanolin derivative, polyoxyethylene 23lauryl ether, polyoxyethylene 23 lauryl ether, polyoxyethylene 2 cetylether, polyoxyethylene 10 cetyl ether, polyoxyethylene 20 cetyl ether,polyoxyethylene 2 stearyl ether, polyoxyethylene 10 stearyl ether,polyoxyethylene 20 stearyl ether, polyoxyethylene 21 stearyl ether,polyoxyethylene 20 oleyl ether, polyoxyethylene 40 stearate,polyoxyethylene 50 stearate, polyoxyethylene 100 stearate, sorbitanmonopalmitate, sorbitan monostearate, sorbitan tristearate,polyoxyethylene 4 sorbitan monostearate, polyoxyethylene 20 sorbitantristearate and mixtures thereof.
 8. A drug formulation as in claim 7,wherein the surfactant is selected from the group consisting of polyoxyl40 stearate, polyoxyl 50 stearate, di-block copolymers of ethyleneoxide:propylene oxide, and a:b:a triblock copolymers of ethyleneoxide:propylene oxide:ethylene oxide.
 9. A drug formulation as in claim4, wherein the low solubility therapeutic drug in the absence ofsolubilizing agent has an aqueous solubility between about 1 μg/ml andabout 50 mg/ml.
 10. A drug formulation as in claim 1, wherein thegranule coating is continuous.
 11. A drug formulation as in claim 1,wherein the granule coating is water-soluble.
 12. A drug formulation asin claim 11, wherein the hydrophillic polymer is selected from the groupconsisting of polyvinyl pyrrolidone, polyethylene oxide, polyethyleneglycol, polyvinyl alcohol, polyvinyl alcohol-polyethylene glycolcopolymer, vinyl acetate-vinyl pyrrolidone copolymer, hydroxypropylcellulose, hydroxypropyl methylcellulose, methylcellulose, hydroxyethylcellulose, sodium carboxymethylcellulose, calciumcarboxymethylcellulose, polyvinyl acetate polyethylene glycolco-polymer, a starch, maltodextrin, a sugar, sorbitol, mannitol,sucrose, gelatin, casein, a natural gum, an alginate or mxtures thereof.13. A drug formulation as in claim 1, wherein the granule coating iswater insoluble.
 14. A drug formulation as in claim 13, wherein thehydrophillic polymer is selected from the group consisting of apolyether, a polyester, cellulose acetate, cellulose acetate butyrate, apolyacrylate and mixtures thereof.
 15. A drug formulation as in claim 1,wherein the granule coating consists of a single layer.
 16. A drugformulation as in claim 15, wherein the single layer granule coatingcomprises a hydrophillic polymer selected from polyvinyl pyrrolidone,polyethylene oxide or methylcellulose.
 17. A drug formulation as inclaim 16, wherein the hydrophillic polymer is methylcellulose.
 18. Adrug formulation as in claim 1, wherein the granule coating comprises amultiplicity of layers.
 19. A drug formulation as in claim 18, whereinthe granule coating consists of two layers.
 20. A drug formulation as inclaim 19, wherein the granule coating comprises an outer coating layerof methylcellulose and an inner coating layer of polyethylene oxide orpolyvinyl pyrrolidone.
 21. A dosage form comprising a drug formulationas in claim 1, wherein the granule comprises a low solubilitytherapeutic drug and wherein the low solubility therapeutic drug istopiramate.
 22. A dosage form comprising (a) a core comprising a firstdrug composition, a second drug composition and a push layer comprisingan osmopolymer; wherein each of the first and second drug compositionscomprise granules having a substrate and a coating, said granulesubstrate comprising a solubilizing agent and a low solubilitytherapeutic drug, and said granule coating comprising a hydrophilicpolymer. (b) a semi-permeable wall surrounding the core; and (c) an exitorifice through the semi-permeable wall for releasing the drugcompositions from the dosage form over a prolonged period of time.
 23. Adosage form as in claim 22, wherein the low solubility therapeutic drugis topiramate.
 24. A dosage form as in claim 23, wherein thesolubilizing agent is a surfactant.
 25. A dosage form as in claim 24,wherein the hydrophilic polymer is methylcellulose.
 26. A dosage formcomprising (a) a core comprising a drug composition, wherein the drugcomposition comprise granules having a substrate and a coating, saidgranule substrate comprising a low solubility therapeutic drug andoptionally a solubilizing agent, and said granule coating comprising oneor more layers, wherein each granule coating layer comprises anindependently selected hydrophilic polymer; (b) a semi-permeable wallsurrounding the core; and (c) an exit orifice through the semi-permeablewall for releasing the drug compositions from the dosage form over aprolonged period of time.
 27. A dosage form as in claim 26, wherein thenumber of granule coating layers is selected to (a) decrease thedissolution rate of the therapeutic drug or (b) increase the time tomaximum release rate of the therapeutic drug or (c) increase the periodof therapeutic drug delivery or (d) decrease the magnitude of themaximum release rate of the therapeutic drug.
 28. A dosage form as inclaim 26, wherein the granule coating comprises one layer and whereinthe hydrophilic polymer is selected to (a) decrease the dissolution rateof the therapeutic drug or (b) increase the time to maximum release rateof the therapeutic drug or (c) increase the period of therapeutic drugdelivery or (d) decrease the magnitude of the maximum release rate ofthe therapeutic drug.
 29. A dosage form as in claim 26, wherein thegranule coating comprises one layer and wherein the amount of saidcoating is selected to (a) decrease the dissolution rate of thetherapeutic drug or (b) increase the time to maximum release rate of thetherapeutic drug or (c) increase the period of therapeutic drug deliveryor (d) decrease the magnitude of the maximum release rate of thetherapeutic drug.
 30. A dosage form as in claim 26, wherein thedissolution rate of the therapeutic drug or the time to maximum releaserate of the therapeutic drug or the period of therapeutic drug deliveryor the magnitude of the maximum release rate of the therapeutic drug iscontrolled by varying one or more of (a) the number of coating granulelayers, (b) the amount of each coating granule layer or (c) thehydrophilic polymer of each coating granule layer.
 31. A dosage form asin claim 26, wherein the low solubility therapeutic drug is topiramate,wherein the granule coating comprises one layer and wherein thehydrophillic polymer is selected from the group consisting ofmethylcellulose, polyvinylpyrolidone and polyethylene oxide.
 32. Adosage form as in claim 31, wherein the amount of granule coating is inthe range of between about 2.5% and about 23% by weight.
 33. A dosageform as in claim 26, wherein the granule coating comprises one layer andthe hydrophilic polymer is selected from the group consisting of (a)methylcellulose in an amount in the range of between about 2.5% andabout 13% by weight, (b) polyvinylpyrolidone in an amount in the rangeof between about 3% and about 23% by weight and (c) polyethylene oxidein an amount in the range of about 5% to about 15% by weight.
 34. Adosage form as in claim 26, wherein the granule coating comprises onelayer and the hydrophilic polymer is methylcellulose in an amount ofabout 3% by weight.